The B9D2 gene comprises four exons (175 amino acids), with the first exon being noncoding. It encodes one of three known B9 domain-containing proteins that are conserved across nearly all ciliated organisms. These proteins localize to the basal body and the ciliary transition zone complex. Studies using model organisms have demonstrated that B9D2 and related proteins play a critical role in ciliogenesis, with disruptions resulting in defective cilia and phenotypes resembling Meckel syndrome (MKS).
To date, five missense variants in B9D2 (NM_030578.3) have been reported in association with ciliopathies:
• Homozygous c.15C>A, p.(His5Gln) — Meckel Syndrome type 10
• Homozygous c.301A>C, p.(Ser101Arg) — Meckel Syndrome type 10
• Compound heterozygous c.463G>A, p.(Gly155Ser) and c.220C>T, p.(Pro74Ser) — Joubert Syndrome type 34
• Homozygous c.107T>C, p.(Leu36Pro) — Joubert Syndrome type 34
Loss of function is the established disease mechanism for these variants. Functional studies indicate that, unlike wild-type B9D2 mRNA, the p.Ser101Arg mutation fails to rescue zebrafish phenotypes caused by b9d2 knockdown. Furthermore, co-immunoprecipitation and mass spectrometry analyses reveal that the p.Ser101Arg mutation disrupts the interaction between B9D2 and MKS1, supporting the conclusion that this variant impairs B9D2 function.
B9D2