Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome.

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Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome.

J Clin Endocrinol Metab. 2017 Apr 27;:

Authors: McCormack SE, Li D, Kim YJ, Lee JY, Kim SH, Rapaport R, Levine MA

Abstract
Context: Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland characterized by the triad of a very thin/interrupted pituitary stalk, an ectopic (or absent) posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland. Complex genetic patterns of inheritance of this disorder are increasingly recognized.
Objective: The objective of this study was to identify a genetic etiology of PSIS in an affected child.
Methods: Whole exome sequencing (WES) was performed using standard techniques, with prioritized genetic variants confirmed via Sanger sequencing. To investigate the effects of one candidate variant on mutant WDR11 function, Western blotting and co-immunofluorescence were used to assess binding capacity, and Leptomycin B exposure along with immunofluorescence were used to assess nuclear localization.
Results: We report a child who presented in infancy with combined pituitary hormone deficiencies whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1 and to localize to the nucleus.
Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism where there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered.

PMID: 28453858 [PubMed - as supplied by publisher]

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