Alternative titles; symbols
HGNC Approved Gene Symbol: SLC27A4
SNOMEDCT: 763401009;
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38) : 9:128,340,527-128,361,470 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Ichthyosis prematurity syndrome | 608649 | Autosomal recessive | 3 |
Using an expression cloning strategy, Schaffer and Lodish (1994) identified a membrane protein, which they termed fatty acid transport protein, or FATP (SLC27A1; 600691), from murine adipocytes. FATP facilitates the uptake of long chain fatty acids. Hirsch et al. (1998) identified a large family of FATPs characterized by the presence of an FATP signature sequence. They identified 5 distinct FATPs in mouse and 6 different FATPs in human, which they designated FATP1 (SLC27A1; 600691), -2 (SLC27A2; 603247), -3 (SLC27A3; 604193), -4 (SLC27A4), -5 (SLC27A5; 603314), and -6 (SLC27A6; 604196). Human and mouse FATPs have unique expression patterns and are found in major organs of fatty acid metabolism, such as adipose tissue, liver, heart, and kidney.
By database analysis, Watkins et al. (2007) identified SLC27A4, which they called ACSVL5. The deduced 643-amino acid protein contains all 5 motifs characteristic of acyl-CoA synthetases. Phylogenetic analysis revealed that ACSVL5 belongs to a family of very long chain acyl-CoA synthetases.
Gertow et al. (2004) stated that the FATP4 gene contains 12 coding exons spanning more than 17 kb of genomic DNA. Watkins et al. (2007) determined that the SLC27A4 gene contains 13 exons.
Gertow et al. (2004) stated that the FATP4 gene maps to chromosome 9q34. Watkins et al. (2007) mapped the SLC27A4 gene to the plus strand of chromosome 9q34.11 by genomic sequence analysis.
Stahl et al. (1999) showed that FATP4 is expressed at high levels on the apical side of mature enterocytes in the small intestine. Furthermore, overexpression of FATP4 in 293 cells facilitated uptake of long chain fatty acids with the same specificity as enterocytes, while reduction of FATP4 expression in primary enterocytes by antisense oligonucleotides inhibited fatty acid uptake by 50%. These results suggested that FATP4 is the principal fatty acid transporter in enterocytes and may constitute a novel target for antiobesity therapy.
Klar et al. (2009) demonstrated that FATP4 deficiency in human fibroblasts is associated with reduced VLCFA-CoA synthetase activity and a reduced incorporation of VLCFA into neutral and polar lipids.
Ichthyosis Prematurity Syndrome
Klar et al. (2009) performed sequence analysis of the FATP4 gene in a North African family, a Middle Eastern family, and 18 families of Scandinavian origin segregating ichthyosis prematurity syndrome (IPS; 608649). They identified 7 different mutations. All affected members of the Scandinavian families were homozygous or compound heterozygous for a nonsense mutation (C168X; 604194.0001), indicating a founder effect. A splice site mutation (604194.0002) and a missense mutation (604194.0007) were identified in homozygosity in affected members of the North African and the Middle Eastern families, respectively. None of the mutations were found in 120 healthy control individuals.
In a 14-year-old Japanese girl with IPS, Tsuge et al. (2015) identified compound heterozygosity for novel missense mutations in the SLC27A4 gene (604194.0008, 604194.0009). The authors stated that this was the first report of a Japanese patient with IPS.
Esperon-Moldes et al. (2019) identified compound heterozygous mutations in the SLC27A4 gene (604194.0010, 604194.0011) in 2 Spanish sisters with IPS.
Insulin Resistance Syndrome
Gertow et al. (2004) investigated polymorphisms in the FATP4 gene with respect to associations with fasting and postprandial lipid and lipoprotein variables and markers of insulin resistance in 608 healthy, middle-aged Swedish men. Heterozygotes for a gly209-to-ser (G209S) polymorphism (ser allele frequency 0.05) had significantly lower body mass index (BMI) and, correcting for BMI, significantly lower triglyceride concentrations, systolic blood pressure, insulin concentrations, and homeostasis model assessment index compared with common (G209) homozygotes. A 3-dimensional model of the FATP4 protein revealed that the variable residue 209 is exposed in a region potentially involved in protein-protein interactions. Furthermore, the model indicated functional regions with respect to nonesterified fatty acid (NEFA) transport and acyl-coenzyme A synthase activity and membrane association. Gertow et al. (2004) concluded that these findings proposed FATP4 as a candidate gene for the insulin resistance syndrome (see 605552) and provided a structural basis for understanding FATP function in NEFA transport and metabolism.
Moulson et al. (2003) discovered a spontaneous autosomal recessive mutation in their mouse colony causing extremely tight, thick skin. They named the mutation 'wrinkle-free' (wrfr). The wrfr phenotype is similar to that of restrictive dermopathy in humans (275210). Newborn wrfr -/- mice have difficulty breathing because of the tight skin, do not suckle, exhibit a defective skin barrier, and die several hours after birth. There are also defects in the hair follicle morphogenesis and hair growth. Moulson et al. (2003) reported positional cloning of the wrfr gene, revealing a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding the fatty acid transport protein FATP4. FATP4 is the primary intestinal fatty acid transport protein and is thought to play a major role in dietary fatty acid uptake. It has therefore been viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. The findings of Moulson et al. (2003) demonstrated an unexpected yet critical role of FATP4 in skin and hair development and suggested that SLC27A4 is a candidate gene for restrictive dermopathy.
In affected members of 18 Scandinavian families segregating ichthyosis prematurity syndrome (IPS; 608649), Klar et al. (2009) identified homozygosity or compound heterozygosity for a c.504C-A transversion in exon 3 of the SLC27A4 gene, resulting in a cys168-to-ter (C168X) substitution. This finding indicates that C168X is a founder mutation. Klar et al. (2009) demonstrated absence of full-length SLC27A4 in an IPS patient homozygous for the mutation. The mutation was not found in 120 healthy control individuals.
In a North African patient with ichthyosis prematurity syndrome (IPS; 608649), daughter to consanguineous parents, Klar et al. (2009) identified a homozygous acceptor splice site mutation for exon 5 (c.716-1G-A) in the SLC27A4 gene, predicting a truncated protein.
In affected members of Scandinavian families segregating ichthyosis prematurity syndrome (IPS; 608649), Klar et al. (2009) identified compound heterozygosity for mutations in the SLC27A4 gene: C168X (604194.0001) and a c.274G-A transition in exon 3, resulting in an ala92-to-thr (A92T) substitution.
In affected members of Scandinavian families segregating ichthyosis prematurity syndrome (IPS; 608649), Klar et al. (2009) identified compound heterozygosity for mutations in the SLC27A4 gene: C168X (604194.0001) and a c.739T-C transition in exon 5, resulting in a ser247-to-pro (S247P) substitution in the highly conserved AMP-binding domain.
In affected members of Scandinavian families segregating ichthyosis prematurity syndrome (IPS; 608649), Klar et al. (2009) identified compound heterozygosity for mutations in the SLC27A4 gene: C168X (604194.0001) and an c.899A-G transition in exon 7, resulting in a gln300-to-arg (Q300R) substitution in the highly conserved AMP-binding domain.
In affected members of Scandinavian families segregating ichthyosis prematurity syndrome (IPS; 608649), Klar et al. (2009) identified compound heterozygosity for mutations in the SLC27A4 gene: C168X (604194.0001) and a c.988-2A-G splice site mutation.
In affected members of a Middle Eastern family with ichthyosis prematurity syndrome (IPS; 608649), Klar et al. (2009) identified homozygosity for a c.1748G-A transition in exon 12 of the SLC27A4 gene, resulting in an arg583-to-his (R483H) mutation in the C-terminal domain.
In a 14-year-old Japanese girl with ichthyosis prematurity syndrome (IPS; 608649), Tsuge et al. (2015) identified compound heterozygosity for novel missense mutations in the SLC27A4 gene: a c.1208G-A transition resulting in a cys403-to-tyr substitution, and a c.1529G-A transition in the conserved very long-chain acyl-CoA synthetases/fatty acid transport proteins (VLACS/FATP) motif resulting in an arg510-to-his substitution (R510H; 604194.0009). The mutations were identified using next-generation sequencing and confirmed by PCR and Sanger sequencing, and were not present in the 1000 Genomes, Exome Variant Server, or Human Genetic Variation databases.
For discussion of the arg510-to-his (R510H) mutation in the SLC27A4 gene that was found in compound heterozygous state in a Japanese girl with ichthyosis prematurity syndrome (IPS; 608649) by Tsuge et al. (2015), see 604191.0008.
In 2 Spanish sisters with ichthyosis prematurity syndrome (IPS; 608649), Esperon-Moldes et al. (2019) identified compound heterozygous mutations in the SLC27A4 gene: a duplication (c.1322dup, NM_005094.3) (rs746178942) resulting in frameshift and premature termination (Gly442ArgfsTer2), and an intronic c.988-19A-G transition (604194.0011). The c.1322dup transcript was present in the patients and their father at an almost undetectable level, determined by capillary electrophoresis. In silico algorithms predicted the c.988-19A-G variant to alter an intronic splicing enhancer site abolishing the binding site for splicing regulatory proteins SRp40 (SRSF5; 600914) and NOVA2 (601991). RT-PCR analysis revealed an aberrant transcript, in-frame delta-8p, in both patients and their mother that lacked the first 45 basepairs of exon 8 (Ile330_Gln344del), which encode the last residues of the ATP/AMP domain. (In the report by Esperon-Moldes et al. (2019), the accession rs746178942 is misassociated with the c.988-19A-G mutation.)
For discussion of the c.988-19A-G mutation (c.988-19A-G, NM_005094.3) in the SLC27A4 gene that was found in compound heterozygous state in 2 sisters with ichthyosis prematurity syndrome (IPS; 608649) by Esperon-Moldes et al. (2019), see 604191.0010.
Esperon-Moldes, U. S., Ginarte, M., Santamarina, M., Rodriguez-Lage, B., Rodriguez-Pazos, L., Vega, A. Novel compound heterozygous FATP4 mutations caused ichthyosis prematurity syndrome in Spanish sisters. Acta Paediat. 108: 763-765, 2019. [PubMed: 30536735] [Full Text: https://doi.org/10.1111/apa.14694]
Gertow, K., Bellanda, M., Eriksson, P., Boquist, S., Hamsten, A., Sunnerhagen, M., Fisher, R. M. Genetic and structural evaluation of fatty acid transport protein-4 in relation to markers of the insulin resistance syndrome. J. Clin. Endocr. Metab. 89: 392-399, 2004. [PubMed: 14715877] [Full Text: https://doi.org/10.1210/jc.2003-030682]
Hirsch, D., Stahl, A., Lodish, H. F. A family of fatty acid transporters conserved from mycobacterium to man. Proc. Nat. Acad. Sci. 95: 8625-8629, 1998. [PubMed: 9671728] [Full Text: https://doi.org/10.1073/pnas.95.15.8625]
Klar, J., Schweiger, M., Zimmerman, R., Zechner, R., Li, H., Torma, H., Vahlquist, A., Bouadjar, B., Dahl. N., Fischer, J. Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome. Am. J. Hum. Genet. 85: 248-253, 2009. [PubMed: 19631310] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.021]
Moulson, C. L., Martin, D. R., Lugus, J. J., Schaffer, J. E., Lind, A. C., Miner, J. H. Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development. Proc. Nat. Acad. Sci. 100: 5274-5279, 2003. [PubMed: 12697906] [Full Text: https://doi.org/10.1073/pnas.0431186100]
Schaffer, J. E., Lodish, H. F. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein. Cell 79: 427-436, 1994. [PubMed: 7954810] [Full Text: https://doi.org/10.1016/0092-8674(94)90252-6]
Stahl, A., Hirsch, D. J., Gimeno, R. E., Punreddy, S., Ge, P., Watson, N., Patel, S., Kotler, M., Raimondi, A., Tartaglia, L. A., Lodish, H. F. Identification of the major intestinal fatty acid transport protein. Molec. Cell 4: 299-308, 1999. [PubMed: 10518211] [Full Text: https://doi.org/10.1016/s1097-2765(00)80332-9]
Tsuge, I., Morishita, M., Kato, T., Tsutsumi, M., Inagaki, H., Mori, Y., Yamawaki, K., Inuo, C., Ieda, K., Ohye, T., Hayakawa, A., Kurahashi, H. Identification of novel FATP4 mutations in a Japanese patient with ichthyosis prematurity syndrome. Hum. Genome Var. 2: 15003, 2015. [PubMed: 27081519] [Full Text: https://doi.org/10.1038/hgv.2015.3]
Watkins, P. A., Maiguel, D., Jia, Z., Pevsner, J. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J. Lipid Res. 48: 2736-2750, 2007. [PubMed: 17762044] [Full Text: https://doi.org/10.1194/jlr.M700378-JLR200]