BBS2 – Ciliopathy

In a cohort of six consanguineous families with clinically diagnosed ciliopathy-like phenotypes, whole exome sequencing identified biallelic loss-of-function variants in BBS2 in three unrelated probands (3 probands; (PMID:28800606)). Variants included c.1932T>G (p.Tyr644Ter), c.1931dup (p.Tyr644Ter), and c.565C>T (p.Arg189Ter), all predicted to truncate the protein. These homozygous variants segregated with disease in each family, confirming an autosomal recessive inheritance mode.

Functional studies corroborate a loss-of-function mechanism. Bbs2(-/-) mice display ventriculomegaly, retinal degeneration, obesity, and abnormal ependymal cilia consistent with human ciliopathy traits (PMID:18032602). In vitro, BBS2 interacts with IFT38 within the IFT-B–BBSome complex, and disruption of this interaction impairs export of the G protein–coupled receptor GPR161 from cilia (PMID:31471295).

Taken together, although human genetic evidence is limited to a single study with three probands, concordant animal and cellular models provide moderate functional support. Key take-home: Biallelic BBS2 loss-of-function variants cause autosomal recessive ciliopathy and warrant inclusion in diagnostic gene panels.

References

• PLoS one • 2017 • Whole exome sequencing as a diagnostic tool for patients with ciliopathy-like phenotypes. PMID:28800606
• Proceedings of the National Academy of Sciences of the United States of America • 2007 • A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. PMID:18032602
• Biology open • 2019 • Requirement of IFT-B–BBSome complex interaction in export of GPR161 from cilia. PMID:31471295

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