Alternative titles; symbols
HGNC Approved Gene Symbol: HOXD13
SNOMEDCT: 719159004, 890439005;
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:176,087,487-176,095,944 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | ?Brachydactyly-syndactyly syndrome | 610713 | 3 | |
| Brachydactyly, type D | 113200 | Autosomal dominant | 3 | |
| Brachydactyly, type E | 113300 | Autosomal dominant | 3 | |
| Syndactyly, type V | 186300 | Autosomal dominant | 3 | |
| Synpolydactyly 1 | 186000 | Autosomal dominant | 3 |
Homeobox (HOX) genes control patterning, differentiation, and morphogenesis during development. HOXD13 is a master regulator of autopod skeletal morphogenesis (summary by Kuss et al., 2014).
D'Esposito et al. (1991) identified 2 novel human homeobox genes located on chromosome 2, upstream from the 7 previously reported ones (see HOXD3; 142980). They designated these 2 genes HOX4H (HOXD12; 142988) and HOX4I (HOXD13).
Muragaki et al. (1996) sequenced the HOXD13 gene and determined that the 5-prime region of the HOXD13 protein contains 2 serine stretches and 1 alanine stretch.
Akarsu et al. (1996) demonstrated that the HOXD13 gene encodes a polypeptide of 335 amino acids that has high homology to the chicken Hoxd13 gene. They noted that the 5-prime end of the gene encodes 15 alanine residues.
Akarsu et al. (1996) analyzed the genomic structure of the HOXD13 gene. They determined that it has 2 exons. Akarsu et al. (1996) reported that the more 3-prime exon encodes the highly conserved homeodomain sequences and that the upstream 757-bp exon and the downstream 248-bp exon are separated by an intron of 950 bp, within which lies a stretch of polymorphic CA repeat sequences.
Brison et al. (2014) stated that sequence comparison of the Hoxd13 gene among different species revealed an additional in-frame start codon, 24 basepairs upstream of the previously proposed first AUG. In earlier reports, the sequence flanked by these 2 AUG codons was thought to be noncoding, but several lines of evidence suggested that this region is protein-coding in higher vertebrates (Nakano et al., 2007; Brison et al., 2012). Brison et al. (2014) noted that later information regarding HOXD13 gene structure in public databases reported the upstream AUG as the in vivo transcription start site, encoding a protein of 343 amino acids rather than 335 and resulting in a change in the numeration of the HOXD13 amino acid sequence.
D'Esposito et al. (1991) identified the HOXD13 gene on chromosome 2.
For a review of the role of this gene in limb development, see Johnson and Tabin (1997).
The anterior to posterior (A-P) polarity of the tetrapod limb is determined by the confined expression of Sonic hedgehog (SHH; 600725) at the posterior margin of developing early limb buds, under the control of HOX proteins encoded by gene members of both the HoxA and HoxD clusters. Tarchini et al. (2006) used a set of partial deletions to show that only the last 4 Hox paralogy groups can elicit this response: i.e., precisely those genes whose expression is excluded from most anterior limb bud cells owing to their collinear transcriptional activation. Deletion of Hoxd10 (142984), Hoxd11 (142986), Hoxd12, and Hoxd13 led to Hoxd9 (142982) upregulation in posterior cells; however, even a robust dose of Hoxd9 was unable to trigger Shh expression, demonstrating that HOXD10-HOXD13 expression is essential to elicit Shh expression. Tarchini et al. (2006) proposed that the limb A-P polarity is produced as a collateral effect of Hox gene collinearity, a process highly constrained by its crucial importance during trunk development. In this view, the co-option of the trunk collinear mechanism, along with emergence of limbs, imposed an A-P polarity to these structures as the most parsimonious solution. This in turn further contributed to stabilize the architecture and operational mode of this genetic system.
Salsi and Zappavigna (2006) identified multiple putative Hox13-binding sites in the mouse Epha7 (602190) promoter and found that Hoxa13 (142959) and Hoxd13 bound 1 of these sites in vivo and that Hoxd13 bound this site in vivo in developing mouse limb.
Montavon et al. (2011) identified 5 conserved regulatory islands dispersed throughout a 600-kb gene desert located 180 kb upstream of the mouse Hoxd13 gene. Crosslinking studies suggested that these elements interacted with and activated Hoxd gene expression via chromatin looping during digit development. Crosslinking frequency was highest for the Hoxd13 region, progressively decreased for Hoxd12 and Hoxd11, and reached background levels for Hoxd8. Expression of Hoxd13 in developing digits was progressively lost with serial deletion of the regulatory islands.
Sheth et al. (2012) used mouse genetics to analyze how digit patterning (an iterative digit/nondigit pattern) is generated and showed that the progressive reduction in Hoxa13 and Hoxd11-Hoxd13 genes (hereafter referred to as distal Hox genes) from the Gli3-null background results in progressively more severe polydactyly, displaying thinner and densely packed digits. Combined with computer modeling, their results argued for a Turing-type mechanism underlying digit patterning, in which the dose of distal Hox genes modulates the digit period or wavelength. The phenotypic similarity of fish-fin endoskeleton patterns suggested that the pentadactyl state has been achieved through modification of an ancestral Turing-type mechanism.
Kherdjemil et al. (2016) showed that the mutually exclusive expression of the mouse genes Hoxa11 (142958) and Hoxa13, which had been proposed to be involved in the origin of the tetrapod limb, is required for the pentadactyl state. Kherdjemil et al. (2016) further demonstrated that the exclusion of Hoxa11 from the Hoxa13 domain relies on an enhancer that drives antisense transcription at the Hoxa11 locus after activation by Hoxa13 and Hoxd13. Finally, the authors showed that the enhancer that drives antisense transcription of the mouse Hoxa11 gene is absent in zebrafish, which, together with the largely overlapping expression of hoxa11 and hoxa13 genes reported in fish, suggested that this enhancer emerged in the course of the fin-to-limb transition. On the basis of the polydactyly that was observed after expression of Hoxa11 in distal limbs, Kherdjemil et al. (2016) proposed that the evolution of Hoxa11 regulation contributed to the transition from polydactyl limbs in stem-group tetrapods to pentadactyl limbs in extant tetrapods.
Akarsu et al. (1996) reported that in 2 unrelated Turkish families with synpolydactyly (SPD1; 186000), duplication of 9 residues of this polyalanine tract (142989.0001) was transmitted from affected parents to their affected offspring but not to their unaffected offspring. This duplication was also found in 2 affected individuals who were recombinant for the HOXD13 CA repeat polymorphism.
Muragaki et al. (1996) found that amplification of the gene region encoding the alanine stretch of HOXD13 showed an additional larger band in the affected individuals in 3 pedigrees with synpolydactyly (186000). Muragaki et al. (1996) noted that the mutation found in these pedigrees did not disrupt an evolutionarily conserved domain.
Warren (1997) suggested that polyalanine expansion found in synpolydactyly by Muragaki et al. (1996) may have resulted from unequal crossing over in the HOXD13 gene. Unlike disorders with trinucleotide repeat expansion, the expanded HOXD13 tract encoding polyalanine was stable when transmitted from one generation to another. Examination of the HOXD13 sequence encoding the polyalanine tract revealed it to be a cryptic repeat of alanine codons GCG, GCA, GCT, and GCC. Such cryptic interruptions are believed to stabilize the repeats at dynamic mutation loci and it had been proposed that tracts of approximately 25 to 35 perfect trinucleotide repeats are required for instability and expansion. Therefore, some similarities exist between polysyndactyly and dynamic mutations at the protein level, but the mechanisms of mutation appear to be different. Muragaki et al. (1996) pointed out that the introduction and lengthening of the polyalanine tract of HOXD13 over evolutionary time may have led to the distinctive limb differences between teleost fish through mammals. Warren (1997) pointed out that many proteins have homopolymer runs of single amino acids that are prone to unequal crossing-over with maintenance of the reading frame. The lengthening of tracts of single amino acids leading to altered or change-of-function proteins may be a common mechanism of human genetic disease.
Goodman et al. (1998) described a novel type of mutation in HOXD13, associated in some cases with features of classic synpolydactyly and in all cases with a novel foot phenotype. In 2 unrelated families, each with a different intragenic deletion in HOXD13 (142989.0002, 142989.0003), all mutation carriers had a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. The 2 different deletions affected the first exon and the homeobox, respectively, producing in each case frameshifts followed by a long stretch of novel sequence and a premature stop codon. Although the mutant forms of the gene may encode proteins that exert a dominant-negative or novel effect, they are most likely to act as null alleles. Either possibility was thought to have interesting implications for the role of HOXD13 in human autopod development. Calabrese et al. (2000) also described a family with a frameshifting deletion of HOXD13, predicted to lead to a truncated protein missing part or all of the homeodomain; hence, the phenotype in these 3 families may be caused by haploinsufficiency. In a family also exhibiting the novel foot malformation with partial duplication of the base of the second metatarsal in the first web space and a broad hallux, Debeer et al. (2002) identified a missense mutation in the homeodomain of HOXD13 (R298W; 142989.0007).
Johnson et al. (2003) stated that 3 distinct classes of mutations had been described in HOXD13: polyalanine tract expansions, truncations, and specific amino acid substitutions. The polyalanine expansion mutations may exert a dominant-negative effect over wildtype protein (Bruneau et al., 2001), and the mutations that truncate the HOXD13 protein are likely to cause loss of function (haploinsufficiency).
In view of the diversity of limb malformations associated with HOXD13 mutations, Johnson et al. (2003) performed a mutation screen of HOXD13 in 128 consecutive patients with unselected congenital limb anomalies who required reconstructive surgery. In 2 probands from large English families segregating an autosomal dominant brachydactyly phenotype with features overlapping brachydactyly types D (BDD; 113200) and E (BDE; 113300), they identified a novel mutation in the homeodomain of HOXD13, ile314 to leu (I314L; 142989.0004). The mutation was associated with the presence of brachydactyly of specific metacarpal or metatarsal bones, a cardinal feature of brachydactyly type E. They therefore sequenced the HOXD13 gene in a family previously classified as having brachydactyly type E by Brailsford (1945) and Oude Luttikhuis et al. (1996) and identified a novel mutation in the homeodomain, ser308 to cys (S308C; 142989.0005). Johnson et al. (2003) noted the wide intrafamilial variation in the hand phenotype in the latter family, which also showed overlap with features of BDD and BDE. They investigated the effect of these mutations on binding of synthetic mutant proteins to the double-stranded DNA targets in vitro. No consistent differences were found for the S308C mutation compared with the wildtype, but the I314L mutation (as position 47 of the homeodomain) exhibited increased affinity for a target containing the core recognition sequence 5-prime-TTAC-3-prime but decreased affinity for a 5-prime-TTAC-3-prime target. Molecular modeling of the I314L mutation indicated that this mixed gain and loss of affinity may be accounted for by the relative positions of methyl groups in the amino acid side chain and target base.
Albrecht et al. (2004) showed that polyalanine repeats of greater than 22 residues were associated with a shift in localization of Hoxd13 from nucleus to cytoplasm, where it formed large amorphous aggregates. Similar aggregates were seen for expansion mutations in SOX3 (313430), RUNX2 (600211), and HOXA13 (142959), pointing to a common mechanism. Cytoplasmic aggregation of mutant Hoxd13 protein was influenced by length of the repeat, level of expression, and efficacy of degradation by the proteasome. Hsp70 (140550) and Hsp40 (604572) colocalized with the aggregates, and activation of the chaperone system by geldanamycin led to a reduction of aggregate formation. Recombinant mutant Hoxd13 protein formed aggregates in vitro demonstrating spontaneous misfolding. In the Spdh mouse, there was a reduction of mutant Hoxd13 and, in contrast to wildtype Hoxd13, a primarily cytoplasmic localization of the protein. Albrecht et al. (2004) concluded that polyalanine repeat expansions in transcription factors may result in misfolding, degradation, and cytoplasmic aggregation of the mutant proteins.
Zhao et al. (2007) reviewed HOXD13, the homeobox-containing gene located at the most 5-prime end of the HOXD cluster. Mutations in human HOXD13 give rise to limb malformations, with variable expressivity in a wide spectrum of clinical manifestations. Polyalanine expansions in HOXD13 cause synpolydactyly (142989.0001), whereas amino acid substitutions in the homeodomain are associated with brachydactyly types D and E (e.g., 142989.0004).
Zhao et al. (2007) described 2 large Han Chinese families with different limb malformations, 1 with syndactyly type V (186300) and the other with limb features overlapping brachydactyly types A4, D, and E with mild syndactyly of toes 2 and 3 (610713). Two-point linkage analysis showed lod scores greater than 3 (theta = 0.0) for markers within and/or flanking the HOXD13 locus in both families. In the family with syndactyly type V, they identified a missense mutation in the HOXD13 homeodomain, gln317 to arg (Q317R; 142989.0009), which led to substitution of the highly conserved glutamine that is important for DNA binding specificity and affinity. In the family with complex brachydactyly and syndactyly, they detected a deletion of 21 bp in the imperfect GCN (where N denotes A, C, G, or T) triplet-containing exon 1 of HOXD13, which results in a polyalanine contraction of 7 residues (142989.0010). Their data established a link between HOXD13 and additional limb phenotypes: syndactyly type V and brachydactyly type A4. It also demonstrated that a polyalanine contraction in HOXD13 probably led to other digital anomalies but not to synpolydactyly. They suggested the term 'HOXD13 limb morphopathies' for the spectrum of limb disorders caused by HOXD13 mutations.
In a large consanguineous Pakistani family with SPD1 mapping to chromosome 2q22.3-q34, Kurban et al. (2011) sequenced the HOXD13 gene and identified a nonsense mutation (Q248X; 142989.0013) that was present in homozygosity in 10 individuals with severe SPD and present in heterozygosity in 12 individuals, 6 of whom had mild SPD and 6 of whom were unaffected.
In a mildly affected mother and severely affected son from a consanguineous Pakistani family with SPD1, Brison et al. (2012) identified heterozygosity and homozygosity, respectively, for a missense mutation in the HOXD13 gene (G11A; 142989.0014). The authors noted that the G11A variant had previously been detected in a screening of Japanese patients with SPD (Nakano et al., 2007). Functional analysis demonstrated that the G11A mutation causes a 5-fold reduction in the intracellular half-life of HOXD13. In addition, the G11A mutant bound the patterning gene GLI3R (see 165240) with higher affinity than wildtype HOXD13 in vitro. Brison et al. (2012) suggested that SPD in patients with the G11A mutation results from depletion of GLI3R levels during early limb development through intracellular protein degradation.
In 6 affected individuals from a 2-generation Chinese family with a variant form of mild SPD, Wang et al. (2012) identified heterozygosity for a missense mutation in the HOXD13 gene (R298Q; 142989.0015), designated as R31Q within the homeodomain. The mutation was shown to impair the capacity of HOXD13 to regulate transcription.
In 5 affected members of a 4-generation Chinese family with SPD as well as broad halluces and cortical bone thinning of the proximal phalanges of the feet, Shi et al. (2013) identified heterozygosity for a splice site mutation (142989.0016) that was not found in 3 unaffected family members or in 60 ethnically matched controls. The mutant showed a significantly lower level of transcriptional activity than wildtype in dual-luciferase assay.
In affected members of a 3-generation Chinese family with mild SPD, consisting of bilateral 3/4 finger webbing and fifth-finger clinodactyly with normal feet, Zhou et al. (2013) identified heterozygosity for a missense mutation outside of the homeobox domain (G220A; 142989.0017).
In a girl exhibiting brachydactyly, syndactyly, and oligodactyly (BDSDO; 610713), Ibrahim et al. (2013) identified heterozygosity for a de novo missense mutation in the HOXD13 gene (Q317K; 142989.0018) that was not found in the dbSNP database. The authors noted that Q317 is conserved in most homeodomains, except for those in bicoid-type homeobox genes such as PITX1 (602149), which have lysine (K) at this position. Expression analysis and functional assays demonstrated that the Q317K mutation results in a partial conversion of HOXD13 into a transcription factor with bicoid/PITX1 properties, whereas another mutation at the same residue, Q317R (142989.0009), does not. Ibrahim et al. (2013) noted that based on traditional analysis of missense mutations, the mutant's failure to bind a consensus motif and activate a reporter would qualify it as a loss-of-function mutation; however, their results suggested that a missense mutation in a transcription factor can act as a gain-of-function mutation that shifts the binding profile of the relevant transcription factor on a genomewide scale.
In 2 unrelated multigenerational Chinese families in which affected individuals exhibited features of synpolydactyly, Dai et al. (2014) sequenced the HOXD13 gene and identified 2 different heterozygous mutations at residue 31 in the homeodomain: R306Q (142989.0015) in a 5-generation family, and R306G (142989.0019) in a 3-generation family. Luciferase assays indicated that both mutations significantly reduced activation of transcription, to approximately 60% and 62% of wildtype, respectively.
Associations Pending Confirmation
For discussion of a possible association between VACTERL association (192350) and mutation in the HOXD13 gene, see 142989.0012.
Johnson et al. (1998) described the phenotype and molecular basis of a spontaneous mutation of Hoxd13 in mice that provided a phenotypically and molecularly accurate model for human synpolydactyly. The new mutation, named synpolydactyly homolog (Spdh), has a 21-bp in-frame duplication within a polyalanine-encoding region of the 5-prime end of the Hoxd13 coding sequence. The duplication expanded the stretch of alanines from 15 to 22; the same type of expansion had been found in human synpolydactyly mutations. Homozygotes exhibited severe malformations of all 4 feet, including polydactyly, syndactyly, and brachydactyly. The phenotype of Spdh was much more severe than that exhibited by mice with a genetically engineered, presumably null disruption of Hoxd13. Thus, Spdh probably acts as a dominant-negative and will be valuable for examining interactions with other HOX genes and their protein products during limb development. Homozygous mice of both sexes also lacked preputial glands and males did not breed; therefore, Spdh/Spdh mice may also be valuable in studies of reproductive physiology and behavior.
Zakany and Duboule (1999) used a Hoxd minicomplex in mice to show that an overlapping, yet different, set of Hoxd genes contributes to the formation of the iliocecal sphincter, which divides the small intestine from the large bowel. See HOXD3 (142980).
Kmita et al. (2002) used targeted meiotic recombination to produce unequal recombination between the HOXD13, HOXD12 (142988), and HOXD11 (142986) loci. Furthermore, some deletions and duplications were engineered along with other mutations in cis. Kmita et al. (2002) found that HOXD genes compete for remote enhancer that recognizes the locus in a polar fashion, with a preference for the 5-prime extremity. Modifications in either the number or topography of HOXD loci induced regulatory reallocations affecting both the number and morphology of digits. These results demonstrated why genes located at the extremity of the cluster are expressed at the distal end of the limbs, following a gradual reduction in transcriptional efficiency, and thus highlighted the mechanistic nature of collinearity in limbs. Kmita et al. (2002) also found that RXII, a DNA fragment that displays sequence conservation with the chicken genome and is located between HOXD13 and EVX2 (142991), was required along with the HOXD13 locus to implement the position-dependent, preferential activation. Removal of both RXII and the HOXD13 locus abrogated quantitative collinearity.
By using an inversion of and a large deficiency in the mouse HoxD cluster, Zakany et al. (2004) found that a perturbation in the early collinear expression of Hoxd11, Hoxd12, and Hoxd13 in limb buds led to a loss of asymmetry. Ectopic Hox gene expression triggered abnormal Shh (600725) transcription, which in turn induced symmetrical expression of Hox genes in digits, thereby generating double posterior limbs. Zakany et al. (2004) concluded that early posterior restriction of Hox gene products sets up an anterior-posterior prepattern, which determines the localized activation of Shh. This signal is subsequently translated into digit morphologic asymmetry by promoting the late expression of Hoxd genes, 2 collinear processes relying on opposite genomic topographies, upstream and downstream Shh signaling.
Kuss et al. (2009) identified Raldh2 (ALDH1A2; 603687), the rate-limiting enzyme for retinoic acid synthesis in mouse limb bud, as a direct Hoxd13 target. Spdh/Spdh mice showed decreased retinoic acid production in limbs, and intrauterine treatment with retinoic acid restored pentadactyly in Spdh/Spdh mice. In wildtype mice, retinoic acid suppressed chondrogenesis in mesenchymal progenitor cells, while Hoxd13 with expanded ala repeats promoted cartilage formation in primary cells isolated from Spdh/Spdh limbs. Increased Sox9 (608160) expression and ectopic cartilage formation in the interdigital mesenchyme of limbs from Spdh/Spdh mice suggested uncontrolled differentiation of these cells into the chondrocytic lineage. Kuss et al. (2009) concluded that mutation of HOXD13 causes polydactyly in synpolydactyly by inducing extraneous interdigital chondrogenesis, both directly and indirectly, via a reduction in retinoic acid levels.
Kuss et al. (2014) observed that spdh embryos exhibited transformation of metacarpals to carpals, with the shape of metacarpals ranging from longitudinal to almost fully round. Most metacarpals had no perichondrium and failed to form cortical bone. Instead, they were surrounded by joint-like structures and underwent secondary ossification similar to that seen in carpal bones. Handplates of spdh embryos showed reduced expression of Wnt5a (164975) and Wnt5b (606361), concomitant with defects in cell polarity in metacarpal growth plates and perichondrium. Visible defects in cell polarity were accompanied by increased staining for the Wnt signaling molecule beta-catenin (CTNNB1; 116806) in perichondral region of metacarpals. Exogenous Hoxd13 and Wnt5a partly rescued cell polarity defects in perichondrium of spdh mice. In vitro, Hoxd13, but not Hoxd13 with the spdh mutation, induced Wnt5a expression. Kuss et al. (2014) concluded that failure of cell polarity in spdh mice leads to transformation of metacarpals to carpal-like structures.
Brison et al. (2012) misexpressed wildtype HOXD13 in the developing limbs of chick embryos and observed marked shortening of the cartilaginous elements of the stylopod and zeugopod, delay in ossification, and premature articulation or fusion of the fibula to the fibulare. The limb defects were classified as mild in 29% of cases, moderate in 42%, and severe in 29%. Misexpression of the HOXD13 G11A mutation (142989.0014) induced similar but more severe skeletal abnormalities, including anterior ectopic cartilage or digit formation in 32% of injected embryos, resembling the phenotype induced by the same mutation in SPD patients. In addition, misexpression of wildtype HOXD13 induced ectopic dHand (602407) expression in 60% of embryos; this effect was more pronounced in embryos injected with the G11A mutant.
In 2 unrelated consanguineous Turkish families with synpolydactyly (SPD1; 186000), one of which was the large kindred originally reported by Sayli et al. (1995), Akarsu et al. (1996) identified a 27-bp duplication in a polyalanine stretch within the N-terminal portion of HOXD13. The duplicated nucleotides were inserted 187 bp downstream of the initiation codon between alanine-14 and alanine-15. The duplication was present in homozygosity in more severely affected individuals, whereas more mildly affected individuals were heterozygous for the duplication, as were 5 unaffected family members. The duplication was not found in 25 Turkish or 50 Caucasian controls. Akarsu et al. (1996) noted that the size of the duplication had remained constant for at least 150 years and over 7 generations in 1 kindred.
Goodman et al. (1997) found that synpolydactyly phenotypes correlate with the size of expansions in the HOXD13 polyalanine tract. Both penetrance and severity of phenotype increase progressively with increasing expansion size. This close correlation, together with the observation that the limb phenotype of mice lacking Hoxd13 is strikingly different from that of humans with SPD (Davis and Capecchi, 1996), led to the suggestion that expansions of the polyalanine tract may confer a progressive gain of function on the mutant protein.
Kjaer et al. (2005) found this +9 alanine expansion in 3 Danish families. They observed striking phenotypic variability in carriers of both this and the ala(7)dup mutation (142989.0008). The observations of a case with purely unilateral syndactyly with broadening of the bones in the fourth finger demonstrated that the phenotype of limbs that have presumably been exposed to the same genetic background and environment can vary from normal to severely affected. This suggested that stochastic fluctuations may also influence the phenotype dramatically.
It is of interest that synpolydactyly was the first disorder in which polyalanine expansion was identified as the disease-causing mechanism. Brown and Brown (2004) and Albrecht and Mundlos (2005) reviewed polyalanine expansion disorders.
In a 6-generation Italian family, Goodman et al. (1998) identified many members in an autosomal dominant pedigree pattern who had features of classic synpolydactyly in the hands and in the feet as well as a novel foot phenotype (SPD1; 186000). All affected individuals (as identified by the presence of the mutation which was found in this family) had a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals as well. Sequence analysis of the HOXD13 gene revealed a 14-bp deletion in exon 1, encompassing bases 323 to 336 of the coding sequence. This deletion began 134 bases downstream of the end of the imperfect trinucleotide repeat sequence that encodes the 15-residue polyalanine tract and affected a region of exon 1 (bases 313 to 330) that encodes a second polyalanine tract, in this case only 6 alanine residues long. The deletion created a frameshift leading to a premature stop codon at bases 681 to 683 of the coding sequence, which would be expected to result in a protein containing only the first 107 amino acids of the wildtype protein, followed by 115 amino acids with no counterpart in the wildtype protein and entirely lacking the homeodomain.
In a 5-generation Scottish family, Goodman et al. (1998) studied affected members with features of classic synpolydactyly in the hands and feet and with a novel foot phenotype consisting of a rudimentary extra digit between the first and second metatarsals and often between the fourth and fifth metatarsals (SPD1; 186000). Sequence analysis of HOXD13 revealed deletion of a single G nucleotide at base 834 of the coding sequence and base 77 of exon 2. The deletion created a frameshift, leading to a premature stop codon at bases 935 to 937 of the coding sequence. The resulting protein would be expected to contain only the first 278 amino acids of the wildtype protein, followed by 33 amino acids with no counterpart in the wildtype protein, and would lack the last 49 amino acids of the 60-amino acid homeodomain, including the entire recognition helix.
Johnson et al. (2003) identified a 940A-C transversion in exon 2 of the HOXD13 gene, resulting in an ile314-to-leu (I314L) mutation, in 18 members from 2 families (10 from one, 8 from the other) who demonstrated phenotypic overlap of brachydactyly types D (BDD; 113200) and E (BDE1; 113300). Apart from moderate generalized brachydactyly, Johnson et al. (2003) found 4 phenotypic patterns associated with the mutation: severe middle finger metacarpal brachydactyly, severe little finger distal phalanx hypoplasia/aplasia, a combination of those 2, and ring finger lateral phalangeal duplication accompanied by three-fourths syndactyly and/or additional features. In 5 of 17 individuals, the phenotype differed between the hands. Most affected individuals had little finger distal phalangeal hypoplasia/aplasia, either alone or in association with other abnormalities, but there were 3 hands with middle finger metacarpal brachydactyly but relatively normal fifth digit distal phalanges. Of 20 feet from molecularly confirmed cases, 8 showed mild clinical abnormalities.
Caronia et al. (2003) identified the I314L mutation in a 6-generation Caucasian English family with a phenotype similar to that reported by Johnson et al. (2003), which Caronia et al. (2003) described as a combination of brachydactyly and central polydactyly. Microsatellite genotyping showed that the affected individuals from the family reported by Caronia et al. (2003) and the 2 families reported by Johnson et al. (2003) shared the same haplotype across the HOXD cluster region, suggesting that the mutation arose in a common ancestor. Caronia et al. (2003) compared the I314L mutant protein both in vitro and in vivo with the wildtype protein and with an artificial HOXD13 mutant that was completely unable to bind DNA. They found that the mutation caused neither a dominant-negative effect nor a gain of function, but instead impaired DNA binding at some sites bound by wildtype HOXD13. Using retrovirus-mediated misexpression in developing chick limbs, they showed that wildtype HOXD13 could upregulate chick EphA7 (602190) in the autopod, but that the I314L mutant form could not. In the zeugopod, however, the mutant form produced striking changes in tibial morphology and ectopic cartilages that were never produced by the artificial HOXD13 mutant, consistent with a selective rather than generalized loss of function. The authors concluded that a mutant HOX protein that recognized only a subset of sites recognized by the wildtype protein caused a novel human malformation, pointing to a hitherto undescribed mechanism by which missense mutations in transcription factors can generate unexpected phenotypes.
Salsi and Zappavigna (2006) found that HOXD13 with the I314L mutation failed to bind and activate the EPHA7 promoter.
Johnson et al. (2003) sequenced the HOXD13 gene in a family previously classified as having brachydactyly type E (BDE1; 113300), and identified a heterozygous 923C-G transversion in exon 2 of the gene, resulting in a ser308-to-cys (S308C) mutation located at the forty-first position of the homeodomain. The mutation segregated in concordance with the phenotype in 9 affected individuals and in 1 unaffected individual at 50% prior risk. The characteristic features were shortening of 1 or more of the metacarpals or metatarsals or of both, often occurring asymmetrically, together with either shortening or elongation of specific distal phalanges (notably the first and fifth) and carpal bone fusion. The hand phenotype showed wide intrafamilial variation of the features, which overlapped those described in brachydactyly types D (BDD; 113200) and E.
Kan et al. (2003) screened for mutations of the HOXD13 gene in patients with a variety of limb malformations. In a 3-generation family without the typical synpolydactyly phenotype in the hands, but with bilateral partial duplication of the second metatarsals within the first web space of the feet (SPD1; 186000), they identified a heterozygous deletion of an adenine at position -2 in the acceptor splice site of exon 2, which they referred to as 758-2delA. Kan et al. (2003) noted that the foot abnormality in this family was similar to that described in 2 families by Goodman et al. (1998) in which different deletions of HOXD13 were found (142989.0002; 142989.0003), and suggested that the distinctive foot phenotype occurs as a result of haploinsufficiency of HOXD13.
In affected members of a 4-generation family with mild features of classic synpolydactyly (SPD1; 186000), Debeer et al. (2002) identified an 892C-T transition in the HOXD13 gene, resulting in an arg298-to-trp (R298W) mutation in the homeodomain of the protein. As arg298 is the thirty-first residue of the HOXD13 homeodomain, the authors referred to this mutation as ARG31TRP. The mutation was thought to destabilize the homeodomain-DNA complex. The digital abnormalities it produced closely resembled those produced by frameshifting deletions in HOXD13. Only 3 of 17 mutation carriers in the family had synpolydactyly, and in all 3 this was unilateral only, whereas none had synpolydactyly in the feet. However, affected members did have partial duplication of the second metatarsals, broad halluces, and hypoplasia or symphalangism of the middle phalanges of the foot. In 13, the only finding was bilateral fifth finger clinodactyly, raising the possibility that some patients with dominantly inherited isolated fifth finger clinodactyly (type A3 brachydactyly; 112700) may harbor mutations in HOXD13. One mutation carrier in the 4-generation family married a member of another family in which hand-foot-genital syndrome (140000) was caused by a polyalanine tract expansion in the HOXA13 gene (142959.0007). The couple produced a girl heterozygous for both mutations who had digital abnormalities strikingly more severe than those in carriers of either individual mutation, indicating that the 2 mutations acted synergistically.
In 1932, Tage Kemp, a distinguished Danish medical/human geneticist, described an extraordinary 5-generation family from the island of Seeland with syndactyly of fingers 3 and 4 and occasional signs of a duplicated finger in the web (Kemp and Ravn, 1932). In the feet, there was syndactyly of toes 4 and 5, sometimes associated with postaxial polydactyly. This form of syndactyly in the classic Kemp kindred was designated syndactyly type V (SDTY5; 186300) by Temtamy and McKusick (1978). Kjaer et al. (2005) reported the updated pedigree of the family reported by Kemp and Ravn (1932) and identified a duplication of 21 bp in the polyalanine-encoding region of the HOXD13 gene. The duplication resulted in an expansion of the polyalanine repeat from 15 to 22 residues.
In a large Han Chinese family, Zhao et al. (2007) found that members with type V syndactyly (SDTY5; 186300) carried a missense mutation in the HOXD13 homeodomain, gln317 to arg (Q317R), caused by a 950A-G transition at nucleotide position 950. The highly conserved gln50 residue is important for DNA binding and specificity. A luciferase reporter assay demonstrated that the Q317R mutant severely impaired the HOXD13 capacity to transactivate the human EPHA7 (602190) promoter, retaining only 13% of the reporter activity compared with the wildtype counterpart.
In a large Han Chinese family, Zhao et al. (2007) found that affected members with a complex brachydactyly-syndactyly syndrome (BDSD; 610713) carried a deletion of 21 basepairs in the HOXD13 gene (157_177del). The deletion was located in the imperfect GCN (where N denotes A, C, G, or T) triplet-containing exon 1 of HOXD13, and resulted in a polyalanine contraction of 7 residues (A53_A59del). The site and length of the polyalanine tract in HOXD13 are highly conserved among mammals. All mammalian HOXD13 proteins with sequences available for analysis had a 15-residue polyalanine tract in their N-terminal region, which suggested to Zhao et al. (2007) a strong functional and structural constraint.
In affected members of a Greek family with synpolydactyly (SPD1; 186000), fifth finger camptoclinodactyly, and occasional fifth toe camptodactyly, Fantini et al. (2009) identified a heterozygous 659T-A transversion in exon 1 of the HOXD13 gene, resulting in a gly220-to-val (G220V) substitution outside of the HOXD13 homeodomain. The G220V mutation caused a significant impairment in HOXD13 DNA-binding activity and transcription regulation. G220V-mutant protein was deficient in both activation and repression of transcription through HOXD13-responsive regulatory elements. In developing chick limbs, misexpression of G220V-mutant protein failed to produce marked proximal limb defects. G220V-mutant protein only moderately upregulated the Hand2 (602407) target gene in embryonic chick limb buds; however, G220V-mutant protein compromised the stability of HOXD13 protein within cells and caused its partial accumulation in the cytosol in the form of subtle aggregates. Fantini et al. (2009) concluded that the G220V mutation represented a dominant loss-of-function mutation, revealing haploinsufficiency of HOXD13.
This variant, formerly titled VACTERL ASSOCIATION, has been reclassified because its contribution to the phenotype has not been confirmed.
In a 17-year-old girl with VACTERL association (192350), Garcia-Barcelo et al. (2008) identified a heterozygous de novo 21-bp deletion (163_183del) in the exon 1 triplet repeats of the HOXD13 gene, resulting in the removal of 7 alanines from the polyalanine tract. She had anal atresia, tetralogy of Fallot, and vesicoureteric reflux. She did not have tracheoesophageal fistula or vertebral abnormalities, but radiographic studies showed fusion of the distal interphalangeal joints of the fourth and fifth toes. Intelligence and development were normal. No polyalanine contractions were found in 192 controls. Garcia-Barcelo et al. (2008) noted that the deletion had the same effect as a 21-bp deletion (157_177del; 142989.0010) observed in a Han Chinese family with a complex brachydactyly-syndactyly syndrome (610713), namely the shortening of the polyalanine tract by 7 residues. Although the authors could not rule out a second mutation elsewhere in the genome as causative for the disorder, the findings suggested that the SHH pathway ma also be involved in the development of gut and genitourinary structures in addition to limb development.
In a large consanguineous Pakistani family with synpolydactyly-1 (SPD1; 186000), Kurban et al. (2011) identified a c.742C-T transition in exon 1 of the HOXD13 gene, resulting in a gln248-to-ter (Q248X) substitution. The mutation was present in homozygosity in 10 individuals with severe SPD and present in heterozygosity in 12 family members, 6 of whom had mild SPD and 6 of whom were unaffected.
In a mildly affected mother and severely affected son from a consanguineous Pakistani family with synpolydactyly (SPD1; 186000), Brison et al. (2012) identified heterozygosity and homozygosity, respectively, for a c.32G-C transversion in exon 1 of the HOXD13 gene, resulting in a gly11-to-ala (G11A) substitution at a highly conserved residue. The authors noted that the G11A variant had previously been detected in a screening of Japanese patients with SPD (Nakano et al., 2007). Brison et al. (2012) performed immunoblotting of transfected COS-7 cells and demonstrated that the G11A mutation causes a 5-fold reduction in the half-life of HOXD13. Misexpression of HOXD13 in chick embryos showed that the G11A mutant induced similar but more severe skeletal abnormalities than wildtype, and there was more pronounced ectopic expression of dHand (602407) expression with the mutant than wildtype. Cotransfection experiments in HEK293 cells demonstrated that the G11A mutant binds GLI3R (see 165240), a repressor of dHand in normal limb prepatterning, with a higher affinity than wildtype HOXD13; the authors also observed that the presence of the G11A mutant significantly reduced the half-life of GLI3R in vitro compared to wildtype. Brison et al. (2012) suggested that SPD in patients with the G11A mutation results from depletion of GLI3R levels during early limb development through intracellular protein degradation.
In 6 affected individuals from a 2-generation Chinese family with synpolydactyly-1 (SPD1; 186000), Wang et al. (2012) identified heterozygosity for a c.893G-A transition in exon 2 of the HOXD13 gene, resulting in an arg298-to-gln (R298Q) substitution. As this mutation occurred within the homeodomain, the authors also referred to this mutation as ARG31GLN (R31Q). The mutation was not found in 2 unaffected family members or in 136 controls. Partial unilateral to complete bilateral cutaneous 3/4 webbing of the fingers was present in all affected individuals; in the proband and 2 other affected individuals, the webbing included fusion of the nails. Wang et al. (2012) stated that the most distinctive manifestation of this mutation was bilateral clinodactyly of the second finger in 3 patients, 1 of whom also had clinodactyly of the second toe. Luciferase assays demonstrated significantly reduced activation of transcription with the mutant compared to wildtype.
In affected members of a 5-generation Chinese family exhibiting features of synpolydactyly, Dai et al. (2014) identified heterozygosity for a c.917G-A transition in exon 2 of the HOXD13 gene, resulting in an arg306-to-gln (ARG306GLN, R306Q) substitution at a highly conserved residue (numbering based on sequence NP_000514.2). The authors also designated this mutation as R31Q within the homeodomain. The mutation was found in 1 clinically unaffected family member, but was not found in 100 healthy controls. Most family members had complete bilateral webbing of fingers 3/4 with fusion of the nails and normal feet; however, 2 affected individuals had normal hands and atypical abnormalities of the feet, including unilateral adduction deformity of the toes in 1 and unilateral partial cutaneous webbing of proximal toes 2/3 in the other. Luciferase assay demonstrated a significant reduction in activation of transcription with the R306Q mutant, to approximately 60% of that of wildtype.
In 5 affected members of a 4-generation Chinese family with mild synpolydactyly as well as broad halluces with cortical bone thinning of the proximal phalanges (SPD1; 186000), Shi et al. (2013) identified heterozygosity for a splice site mutation (c.781+1G-A) that activates a cryptic splice site, resulting in skipping of the last 214 nucleotides of exon 1, causing a frameshift and creating a premature stop codon (Gly190fsTer4). The mutation was not found in 3 unaffected family members or in 60 ethnically matched controls. The mutant showed a significantly lower level of transcriptional activity than wildtype in dual-luciferase assay.
In affected members of a 3-generation Chinese family with mild synpolydactyly-1 (SPD1; 186000), consisting of bilateral 3/4 finger webbing and fifth-finger clinodactyly with normal feet, Zhou et al. (2013) identified heterozygosity for a c.659G-C transversion in exon 1 of the HOXD13 gene, resulting in a gly220-to-ala (G220A) substitution outside of the homeobox domain.
In a girl exhibiting brachydactyly, syndactyly, and oligodactyly (BDSDO; see 610713), Ibrahim et al. (2013) identified heterozygosity for a de novo c.949C-A transversion (c.949C-A, NM_000523.2) in exon 2 of the HOXD13 gene, resulting in a gln317-to-lys (Q317K) substitution in the homeodomain. The mutation was not found in the dbSNP database. The authors noted that Q317 is conserved in most homeodomains, except for those in bicoid-type homeobox genes such as PITX1 (602149), which have lysine (K) at this position. Expression analysis and functional assays demonstrated that the Q317K mutant recognizes the PITX1 binding site, causing a partial conversion of HOXD13 into a transcription factor with bicoid/PITX1 properties.
In affected members of a 3-generation Chinese family exhibiting features of synpolydactyly (SPD1; 186000), Dai et al. (2014) identified heterozygosity for a c.916G-C transversion in exon 2 of the HOXD13 gene, resulting in an arg306-to-gly (R306G) substitution at a highly conserved residue. This mutation was designated R31G within the homeodomain. The mutation was not found in unaffected family members or in 100 healthy controls. Most family members had complete bilateral 3/4 webbing of the fingers with normal feet, but 1 affected individual showed unilateral 4/5 synpolydactyly of the toes and unilateral cutaneous 3/4 webbing of the fingers. Luciferase assay demonstrated a significant reduction in activation of transcription with the R306G mutant, to approximately 62% of that of wildtype.
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