#620438
Table of Contents
A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-51 (CILD51) is caused by homozygous or compound heterozygous mutation in the BRWD1 gene (617824) on chromosome 21q22.
Primary ciliary dyskinesia-51 (CILD51) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), resulting in severely reduced progressive motility. Some men also have a low sperm count. In addition, affected individuals experience chronic rhinosinusitis and bronchitis, and recurrent upper and lower respiratory infections, and some exhibit dextrocardia and/or situs inversus (Guo et al., 2021).
For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).
Guo et al. (2021) reported 3 unrelated Chinese men (F1, F2, and F3) with infertility due to MMAF as well as chronic respiratory illnesses, and mutation in the BRWD1 gene. Semen analysis in all 3 men revealed severely reduced progressive sperm motility, with increased percentages of abnormal flagella, including absent, short, and irregular-caliber flagella. Probands F2 and F3 also showed markedly reduced sperm counts. Transmission electron microscopy (TEM) of patient sperm (from F1 and F2) showed absence of the inner and outer dynein arms (IDAs and ODAs), and this was confirmed by immunostaining; however, the outer doublet microtubule (DMT) number and central pair complex were normal. All 3 men also had a history of chronic wet cough, nasal obstruction, and pneumonia early in life, which developed into chronic rhinosinusitis and bronchitis and recurrent upper and lower respiratory tract infections in adulthood. CT of the paranasal sinuses in F1 and F2 confirmed chronic rhinosinusitis with a narrowed sinus cavity. Chest CT revealed bronchiectasis and dextrocardia in both, and F1 also had situs inversus. Nasal nitric oxide testing in F1, who had relatively more severe respiratory symptoms than the other 2 probands, showed a level below the diagnostic cutoff for primary ciliary dyskinesia, whereas nasal nitric oxide in F2 was normal; F3 was not tested. TEM of respiratory cilia from patient F1 revealed defects in the IDAs and ODAs as well as a frequent absence of outer DMTs (ranging from 8+2 to 5+2). Staining for markers of the ODAs confirmed their absence in respiratory epithelial cells from F1. In addition, the overall number of cilia was decreased in F1, and cilia on the free surface of respiratory epithelial cells were notably shorter and fewer than those of healthy controls.
The transmission pattern of CILD51 in the families reported by Guo et al. (2021) was consistent with autosomal recessive inheritance.
In a cohort of 53 infertile Chinese men with MMAF and respiratory symptoms consistent with primary ciliary dyskinesia, who were negative for mutation in known male infertility-associated genes, Guo et al. (2021) performed exome sequencing and identified biallelic missense mutations in 3 unrelated men (see, e.g., 617824.0001 and 617824.0002). The mutations segregated with disease in all 3 families and were not found in 442 Han Chinese controls, including 219 men with isolated oligoasthenozoospermia and 223 fertile controls. The mutations either were not found or were present at very low minor allele frequency in public variant databases.
Pattabiraman et al. (2015) generated Brwd1 -/- mice, noting that both mutant males and mutant females are infertile. The authors found that loss of Brwd1 causes a sexually dimorphic phenotype in male and female germ cells due to very different underlying mechanisms: in males, meiotic division is unaffected, but spermiogenesis is abnormal, whereas in females, the oocyte-to-embryo transition is blocked. Microarray analysis of wildtype and mutant testes revealed that approximately 300 genes were misregulated in Brwd1 -/- mutants; the ontologies and functions of those genes included spermatogenesis, cytoskeletal dynamics, flagellar formation, chromatin organization, sperm motility, protein dynamics, and metabolic pathways, consistent with the Brwd1 mutant phenotype. FLAG-tagged BRWD1 associated with chromatin when expressed in HEK cells; the authors suggested that BRWD1 might be part of unique postmeiotic transcriptional-activator complexes that interact with acetylated histones around postmeiotic genes.
Guo, T., Tu, C.-F., Yang, D.-H., Ding, S.-Z., Lei, C., Wang, R.-C., Liu, L., Kang, X., Shen, X.-Q., Yang, Y.-F., Tan, Z.-P., Tan, Y.-Q., Luo, H. Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia. Hum. Genet. 140: 761-773, 2021. [PubMed: 33389130, related citations] [Full Text]
Pattabiraman, S., Baumann, C., Guisado, D., Eppig, J. J., Schimenti, J. C., De La Fuente, R. Mouse BRWD1 is critical for spermatid postmeiotic transcription and female meiotic chromosome stability. J. Cell Biol. 208: 53-69, 2015. [PubMed: 25547156, images, related citations] [Full Text]
ORPHA: 244; MONDO: 0957396;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 21q22.2 | Ciliary dyskinesia, primary, 51 | 620438 | Autosomal recessive | 3 | BRWD1 | 617824 |
A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-51 (CILD51) is caused by homozygous or compound heterozygous mutation in the BRWD1 gene (617824) on chromosome 21q22.
Primary ciliary dyskinesia-51 (CILD51) is characterized by male infertility due to multiple morphologic abnormalities of the sperm flagella (MMAF), resulting in severely reduced progressive motility. Some men also have a low sperm count. In addition, affected individuals experience chronic rhinosinusitis and bronchitis, and recurrent upper and lower respiratory infections, and some exhibit dextrocardia and/or situs inversus (Guo et al., 2021).
For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).
Guo et al. (2021) reported 3 unrelated Chinese men (F1, F2, and F3) with infertility due to MMAF as well as chronic respiratory illnesses, and mutation in the BRWD1 gene. Semen analysis in all 3 men revealed severely reduced progressive sperm motility, with increased percentages of abnormal flagella, including absent, short, and irregular-caliber flagella. Probands F2 and F3 also showed markedly reduced sperm counts. Transmission electron microscopy (TEM) of patient sperm (from F1 and F2) showed absence of the inner and outer dynein arms (IDAs and ODAs), and this was confirmed by immunostaining; however, the outer doublet microtubule (DMT) number and central pair complex were normal. All 3 men also had a history of chronic wet cough, nasal obstruction, and pneumonia early in life, which developed into chronic rhinosinusitis and bronchitis and recurrent upper and lower respiratory tract infections in adulthood. CT of the paranasal sinuses in F1 and F2 confirmed chronic rhinosinusitis with a narrowed sinus cavity. Chest CT revealed bronchiectasis and dextrocardia in both, and F1 also had situs inversus. Nasal nitric oxide testing in F1, who had relatively more severe respiratory symptoms than the other 2 probands, showed a level below the diagnostic cutoff for primary ciliary dyskinesia, whereas nasal nitric oxide in F2 was normal; F3 was not tested. TEM of respiratory cilia from patient F1 revealed defects in the IDAs and ODAs as well as a frequent absence of outer DMTs (ranging from 8+2 to 5+2). Staining for markers of the ODAs confirmed their absence in respiratory epithelial cells from F1. In addition, the overall number of cilia was decreased in F1, and cilia on the free surface of respiratory epithelial cells were notably shorter and fewer than those of healthy controls.
The transmission pattern of CILD51 in the families reported by Guo et al. (2021) was consistent with autosomal recessive inheritance.
In a cohort of 53 infertile Chinese men with MMAF and respiratory symptoms consistent with primary ciliary dyskinesia, who were negative for mutation in known male infertility-associated genes, Guo et al. (2021) performed exome sequencing and identified biallelic missense mutations in 3 unrelated men (see, e.g., 617824.0001 and 617824.0002). The mutations segregated with disease in all 3 families and were not found in 442 Han Chinese controls, including 219 men with isolated oligoasthenozoospermia and 223 fertile controls. The mutations either were not found or were present at very low minor allele frequency in public variant databases.
Pattabiraman et al. (2015) generated Brwd1 -/- mice, noting that both mutant males and mutant females are infertile. The authors found that loss of Brwd1 causes a sexually dimorphic phenotype in male and female germ cells due to very different underlying mechanisms: in males, meiotic division is unaffected, but spermiogenesis is abnormal, whereas in females, the oocyte-to-embryo transition is blocked. Microarray analysis of wildtype and mutant testes revealed that approximately 300 genes were misregulated in Brwd1 -/- mutants; the ontologies and functions of those genes included spermatogenesis, cytoskeletal dynamics, flagellar formation, chromatin organization, sperm motility, protein dynamics, and metabolic pathways, consistent with the Brwd1 mutant phenotype. FLAG-tagged BRWD1 associated with chromatin when expressed in HEK cells; the authors suggested that BRWD1 might be part of unique postmeiotic transcriptional-activator complexes that interact with acetylated histones around postmeiotic genes.
Guo, T., Tu, C.-F., Yang, D.-H., Ding, S.-Z., Lei, C., Wang, R.-C., Liu, L., Kang, X., Shen, X.-Q., Yang, Y.-F., Tan, Z.-P., Tan, Y.-Q., Luo, H. Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia. Hum. Genet. 140: 761-773, 2021. [PubMed: 33389130] [Full Text: https://doi.org/10.1007/s00439-020-02241-4]
Pattabiraman, S., Baumann, C., Guisado, D., Eppig, J. J., Schimenti, J. C., De La Fuente, R. Mouse BRWD1 is critical for spermatid postmeiotic transcription and female meiotic chromosome stability. J. Cell Biol. 208: 53-69, 2015. [PubMed: 25547156] [Full Text: https://doi.org/10.1083/jcb.201404109]
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