Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome

Abstract

Context: Pituitary stalk interruption syndrome (PSIS) is a rare, congenital anomaly of the pituitary gland characterized by pituitary gland insufficiency, thin or discontinuous pituitary stalk, anterior pituitary hypoplasia, and ectopic positioning of the posterior pituitary gland (neurohypophysis). The clinical presentation of patients with PSIS varies from isolated growth hormone (GH) deficiency to combined pituitary insufficiency and accompanying extrapituitary findings. Mutations in HESX1, LHX4, OTX2, SOX3, and PROKR2 have been associated with PSIS in less than 5% of cases; thus, the underlying genetic etiology for the vast majority of cases remains to be determined.

Objective: We applied whole-exome sequencing (WES) to a consanguineous family with two affected siblings who have pituitary gland insufficiency and radiographic findings of hypoplastic (thin) pituitary gland, empty sella, ectopic neurohypophysis, and interrupted pitiutary stalk-characteristic clinical diagnostic findings of PSIS.

Design and participants: WES was applied to two affected and one unaffected siblings.

Results: WES of two affected and one unaffected sibling revealed a unique homozygous missense mutation in GPR161, which encodes the orphan G protein-coupled receptor 161, a protein responsible for transducing extracellular signals across the plasma membrane into the cell.

Conclusion: Mutations of GPR161 may be implicated as a potential novel cause of PSIS.

Figure 1.

Facial images, extremity pictures, and hypophysis MRIs of the patients. A–D, Pictures of both affected siblings show hypotelorism, sparse hair on the frontal region, broad nasal root, and thick ala nasi. E–H, Hypophysis MRI reveals thin pituitary gland together with ectopic neurohypophysis and interrupted stalk. I–N, Pictures of hands and feet show partial syndactyly of second and third toes and hypoplastic nails.

Figure 2.

Pedigree of the family, segregation study, and AOH regions. A, Pedigree of the family. Black filled boxes indicate affected individuals. Individual identification numbers are written in the left column starting with BAB. B, Sanger chromatographs of the entire family for segregation analyses. Affected individuals have homozygous mutation whereas unaffected individuals are heterozygous or wild type, which is consistent with Mendelian recessive expectations. C, AOH study based on data culled from WES. Gray shaded areas indicate AOH regions. Note that the GPR161 mutation is located in the ∼7.2 Mb block of AOH region in both affecteds, but not in the unaffected sibling.

Figure 3.

Role of GPR161 receptor in connection with GLI-Kruppel family member proteins and Shh signaling. A, GPR161 acts in the Shh signaling pathway; it is a regulator of the PKA-dependent basal repression machinery and functions by increasing cAMP levels. This eventually leads to proteolytic processing of Gli transcription factors (GLI2 and GLI3) into Gli repressor forms, which repress the Shh signaling pathway. B, p.Leu19Gln is predicted as “probably damaging” by Polyphen2; p.L19Q occurs at the extracellular region of the protein potentially assisting ligand binding. GPR161's protein structure was modeled by GPCR-I-TASSER server.