Alternative titles; symbols
HGNC Approved Gene Symbol: DCAF17
SNOMEDCT: 816067005;
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38) : 2:171,434,226-171,485,052 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Woodhouse-Sakati syndrome | 241080 | Autosomal recessive | 3 |
Alazami et al. (2008) identified the C2ORF37 gene within a region of chromosome 2 to which they had mapped the locus for the hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome, also known as Woodhouse-Sakati syndrome (WDSKS; 241080). The gene displays extreme splicing variability, including 2 major variants, called alpha and beta, that encode proteins of 240 and 520 amino acids, respectively. The alpha isoform is identical to the last 240 amino acids of the beta isoform. Real-time RT-PCR of various adult human tissues revealed low ubiquitous expression of both variants. Immunohistochemical analysis showed nearly ubiquitous nucleolar expression of C2orf37 in mouse embryos, with enhanced staining in brain, liver, and skin. Both the alpha and beta isoforms of endogenous C2ORF37 colocalized with the nucleolar phosphoprotein B23 (NPM1; 164040) in human embryonic kidney (HEK293) cells.
Alazami et al. (2008) determined that the C2ORF37 gene contains at least 14 exons.
By genomic sequence analysis, Alazami et al. (2008) mapped the DCAF17 gene to chromosome 2q22.3-q35.
By subjecting HEK293 cells to low and high doses of actinomycin D, a powerful inhibitor of transcription, Alazami et al. (2008) showed that the nucleolar localization of the alpha and beta isoforms of C2ORF37 is only partially dependent on active transcription. They found that in normal control lymphoblasts, C2ORF37 and B23 migrated from the nucleolar compartment to the nucleoplasm after high-dose actinomycin D treatment, but remained largely nucleolar at lower doses. In contrast, in lymphoblasts from patients with WDSKS, C2ORF37 and B23 migrated to the nucleoplasmic compartment after low-dose actinomycin D treatment, suggesting enhanced sensitivity to transcriptional blockade.
In 8 Saudi families with an extrapyramidal movement disorder associated with hypogonadism, alopecia, diabetes mellitus, and mental retardation, also known as Woodhouse-Sakati syndrome (WDSKS; 241080), including 1 of the original families described by Woodhouse and Sakati (1983), Alazami et al. (2008) identified homozygosity for a 1-bp deletion in the C2ORF37 gene (612515.0001). The authors subsequently identified homozygosity for a different 1-bp deletion and 2 splice site mutations in the C2ORF37 gene in 3 additional families of varying ethnicities with WDSKS, respectively (see 612515.0002-612515.0004). The mutations segregated fully with disease in all of the families and were not found in ethnically matched controls. The 2 splice site mutations were predicted to be pathogenic for both major transcripts, whereas the 2 deletion mutations were predicted to affect only the beta-isoform.
Alazami et al. (2010) analyzed the C2ORF37 gene in 7 patients with Woodhouse-Sakati syndrome from 4 unrelated families, 2 of Italian origin, 1 of French-Gypsy origin, and 1 of Turkish origin, and identified homozygosity for 3 nonsense mutations (612515.0005-612515.0007, respectively) and 1 deletion/insertion (612515.0008). Screening of the C2ORF37 gene in a cohort of 11 patients with deafness and dystonia but no hypogonadism, alopecia, or mental retardation did not reveal any mutations, suggesting that mutation in C2ORF37 does not contribute significantly to cases presenting with isolated elements of Woodhouse-Sakati syndrome. Alazami et al. (2010) found no correlation between clinical expressivity and site of mutation, and noted that the intrafamilial variability in the mutation-positive patients indicated that modifiers likely play an important role in this disease.
In 7 affected members of 2 Saudi families with Woodhouse-Sakati syndrome (WDSKS; 241080), including 1 of the original families described by Woodhouse and Sakati (1983), Alazami et al. (2008) identified homozygosity for a 1-bp deletion (436delC) in exon 4 of the DCAF17 gene, predicted to cause a frameshift in the beta-isoform of the protein and result in premature termination. The authors stated that in the alpha-isoform, the 1-bp deletion was predicted to lie in the 5-prime UTR and was unlikely to be pathogenic. The mutation was subsequently identified in 6 additional Saudi families with the disorder, but not in 274 Saudi control chromosomes. SNP-based haplotype analysis confirmed a founder effect, and the deletion likely arose approximately 55 generations earlier.
In a 52-year-old Eastern European woman with Woodhouse-Sakati syndrome (WDSKS; 241080), previously reported by Medica et al. (2007), Alazami et al. (2008) identified homozygosity for a 1-bp deletion (50delC) in exon 1b of the DCAF17 gene, predicted to cause a frameshift in the beta-isoform of the protein only. The mutation was not found in 210 Slovenian control chromosomes.
In 3 affected sibs from a consanguineous Indian family with Woodhouse-Sakati syndrome (WDSKS; 241080), previously reported by Koshy et al. (2008), Alazami et al. (2008) identified homozygosity for a G-T transversion at a splice site in intron 13 of the DCAF17 gene (1422+5G-T), predicted to change the consensus donor sequence and result in a dramatic drop in splicing efficiency. The mutation was not found in 196 Indian control chromosomes.
In 2 affected sibs from a consanguineous Middle Eastern family with Woodhouse-Sakati syndrome (WDSKS; 241080), previously reported by Schneider and Bhatia (2008), Alazami et al. (2008) identified homozygosity for a T-G transversion at a splice site in intron 10 of the DCAF17 gene (1091+6T-G), predicted to cause skipping of exon 10 and result in a frameshift. The mutation was not found in 250 Middle Eastern control chromosomes.
In 3 sibs from a consanguineous family of French-Gypsy origin with Woodhouse-Sakati syndrome (WDSKS; 241080), Alazami et al. (2010) identified homozygosity for a 387G-A transition in exon 4 of the DCAF17 gene, resulting in a trp129-to-ter (W129X) substitution. The affected 15-year-old brother had alopecia, pubertal delay, mild sensorineural deafness, and mild cognitive impairment. His affected sisters, who were 13 and 12 years old, respectively, had alopecia and pubertal delay, but no hearing or cognitive impairment. The boy had hypogonadotropic hypogonadism, whereas his 2 sisters had hypergonadotropic hypogonadism. None of the sibs responded to usual doses of steroid treatment, but they had slow and limited responses to high-dose hormone replacement. None of the sibs displayed dystonia or diabetes.
In a 58-year-old Italian man with Woodhouse-Sakati syndrome (WDSKS; 241080), Alazami et al. (2010) identified homozygosity for a 906G-A transition in exon 9 of the DCAF17 gene, resulting in a trp302-to-ter (W302X) substitution. The proband exhibited the full constellation of hypogonadism, alopecia, diabetes mellitus, cognitive impairment, and dystonia. His sister, who was reported to have died at 46 years of age of myocardial infarction and heart block, had autopsy findings that suggested the presence of alopecia and hypogonadism. There was also a distant female relative in this pedigree who had similar clinical features to those of the proband. Steindl et al. (2010) provided additional clinical details on this family, noting that all 3 affected individuals had anodontia from an early age.
In a 41-year-old Italian woman with Woodhouse-Sakati syndrome (WDSKS; 241080), who was born of first-cousin parents, Alazami et al. (2010) identified homozygosity for a 341C-A transversion in exon 4 of the DCAF17 gene, resulting in a ser114-to-ter (S114X) substitution. The patient presented for evaluation of primary amenorrhea, progressive alopecia, and hearing loss; she also developed type 1 diabetes in her early thirties, and was assessed to have mild developmental disability with deterioration from previously higher function. She had a similarly affected younger sib, who had hypogonadism, alopecia, diabetes mellitus, cognitive impairment, and hearing loss.
In a 36-year-old man of Turkish origin with Woodhouse-Sakati syndrome (WDSKS; 241080), who was born of first-cousin parents, Alazami et al. (2010) identified homozygosity for a 3-bp deletion/2-bp insertion (127delTAGinsAA) that replaces the last 3 basepairs of intron 1 of the DCAF17 gene and is predicted to result in aberrant splicing. The proband stated that he had an affected brother and 2 affected sisters who shared his phenotype of alopecia, cognitive impairment, and dystonia. Additional features in the proband included hypothyroidism and infertility due to azoospermia.
Alazami, A. M., Al-Saif, A., Al-Semari, A., Bohlega, S., Zlitni, S., Alzahrani, F., Bavi, P., Kaya, N., Colak, D., Khalak, H., Baltus, A., Peterlin, B., Danda, S., Bhatia, K. P., Schneider, S. A., Sakati, N., Walsh, C. A., Al-Mohanna, F., Meyer, B., Alkuraya, F. S. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am. J. Hum. Genet. 83: 684-691, 2008. [PubMed: 19026396] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.018]
Alazami, A. M., Schneider, S. A., Bonneau, D., Pasquier, L., Carecchio, M., Kojovic, M., Steindl, K., de Kerdanet, M., Nezarati, M. M., Bhatia, K. P., Degos, B., Goh, E., Alkuraya, F. S. C2orf37 mutational spectrum in Woodhouse-Sakati syndrome patients. Clin. Genet. 78: 585-590, 2010. [PubMed: 20507343] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01441.x]
Koshy, G., Danda, S., Thomas, N., Mathews, V., Viswanathan, V. Three siblings with Woodhouse-Sakati syndrome in an Indian family. Clin. Dysmorph. 17: 57-60, 2008. [PubMed: 18049083] [Full Text: https://doi.org/10.1097/MCD.0b013e3282beb59e]
Medica, I., Sepcic, J., Peterlin, B. Woodhouse-Sakati syndrome: case report and symptoms review. Genet. Counsel. 18: 227-231, 2007. [PubMed: 17710875]
Schneider, S. A., Bhatia, K. P. Dystonia in the Woodhouse Sakati syndrome: a new family and literature review. Mov. Disord. 23: 592-596, 2008. [PubMed: 18175354] [Full Text: https://doi.org/10.1002/mds.21886]
Steindl, K., Alazami, A. M., Bhatia, K. P., Wuerfel, J. T., Petersen, D., Cartolari, R., Neri, G., Klein, C., Mongiardo, B., Alkuraya, F. S., Schneider, S. A. A novel C2orf37 mutation causes the first Italian cases of Woodhouse Sakati syndrome. (Letter) Clin. Genet. 78: 594-597, 2010. [PubMed: 21044051] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01447.x]
Woodhouse, N. J. Y., Sakati, N. A. A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities. J. Med. Genet. 20: 216-219, 1983. [PubMed: 6876115] [Full Text: https://doi.org/10.1136/jmg.20.3.216]