GPR161 – Pituitary Stalk Interruption Syndrome

GPR161 has been implicated in Pituitary Stalk Interruption Syndrome based on a consanguineous family with two siblings exhibiting anterior pituitary hypoplasia and interrupted stalk. Whole-exome sequencing revealed a homozygous upstream variant, c.-5T>A, in GPR161 segregating with disease in both siblings (2 probands)[PMID:25322266]. No additional unrelated cases or extended segregation data are available, and the variant lies outside the coding region, limiting the genetic evidence.

GPR161 encodes a primary ciliary orphan G protein-coupled receptor that transduces extracellular signals to regulate Hedgehog signaling. Mouse Gpr161 null and hypomorphic models exhibit severe developmental defects, including neural tube closure failure, supporting a role for GPR161 in embryonic patterning though direct pituitary studies are lacking[PMID:18250320]. This mechanistic concordance suggests a loss-of-function mechanism in PSIS.

Key Take-home: Current evidence is limited but supports GPR161 c.-5T>A homozygosity as a candidate cause of PSIS; inclusion of GPR161 in genetic testing panels for congenital pituitary disorders may aid diagnosis.

References

• The Journal of clinical endocrinology and metabolism • 2015 • Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. PMID:25322266
• Proceedings of the National Academy of Sciences of the United States of America • 2008 • The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. PMID:18250320

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