Molecular characteristics
The C2orf37 or DCAF17 (DDB1- And CUL4-Associated Factor 17) gene is located at 2q31.1 and includes two major variants, alpha and beta, which encodes proteins of 240 and 520 amino acids, respectively. The proteins localize to the nucleolus and have a poorly understood function. The gene expression is ubiquitous, with enhanced expression in the brain, liver, and skin of mouse embryos.
Mutations and pathophysiology
Alazami et al. (2010) found an apparent lack of correlation between the site of mutation and the clinical expressivity, suggesting that the presence of a full-length protein is necessary for functionality. Intrafamilial variability suggests an important role of modifiers in the pathogenesis of Woodhouse-Sakati syndrome. The pathogenic mechanism underlying the syndrome is not yet known, but it has been hypothesized that defective ribosomal biogenesis or other nucleolar dysfunction may explain it.
More than 50 cases of Woodhouse-Sakati syndrome have been reported. The following are some selected examples of the pathogenic variants in DCAF17:
Alazami et al. (2008) reported homozygosity for the following mutations in DCAF17 gene:
- 1 bp deletion (c.436delC) in exon 4 leading to frameshift and premature termination of the beta-isoform of the protein. The 7 affected members came from two Saudi consanguineous families.
- 1 bp deletion (50delC) in exon 1b leading to frameshift in the beta-isoform of the protein. The affected patient is of an Eastern-European origin.
- 1422+5G>T mutation affecting a splice donor site and resulting in a significant drop in splicing efficiency. The mutation affected three siblings from a consanguineous Indian family.
- 1091+6T>G mutation affecting a splice donor site and resulting in the skipping of exon 10, leading to a frameshift. The two affected siblings came from a consanguineous Middle Eastern family.
Alazami et al. (2010) reported seven new cases from four unrelated families with features consistent with Woodhouse-Sakati syndrome:
- 127-3delTAGinsAA mutation resulting in aberrant splicing. The mutation affected a man of Turkish consanguineous family.
- A nonsense base substitution (c.341C>A) in exon 4 resulting in a stop codon (p.S114X). The affected individual came from an Italian consanguineous family.
- 387G>A in exon 4 resulting in p.W129X. The mutation affected three siblings form a consanguineous French-Gypsy family.
- A nonsense c.906G>A mutation in exon 9 causing a p.W302X termination codon. The affected individual came from an Italian consanguineous family.