Clinical and Functional Characterization of a Patient Carrying a Compound Heterozygous Pericentrin Mutation and a Heterozygous IGF1 Receptor Mutation

Eva Müller,Desiree Dunstheimer,Tassilo Kruis,Jürgen Klammt,Peter H Heidemann,Roland Pfäffle,Sandy Laue,Jürgen Kratzsch,Wieland Kiess,Tillmann Wallborn,Daniela Friebe,Hironori Waki

doi:10.1371/journal.pone.0038220

Eva Müller, Desiree Dunstheimer + Show 10 more

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https://doi.org/10.1371/journal.pone.0038220

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Abstract

Intrauterine and postnatal longitudinal growth is controlled by a strong genetic component that regulates a complex network of endocrine factors integrating them with cellular proliferation, differentiation and apoptotic processes in target tissues, particularly the growth centers of the long bones. Here we report on a patient born small for gestational age (SGA) with severe, proportionate postnatal growth retardation, discreet signs of skeletal dysplasia, microcephaly and moyamoya disease. Initial genetic evaluation revealed a novel heterozygous IGF1R p.Leu1361Arg mutation affecting a highly conserved residue with the insulin-like growth factor type 1 receptor suggestive for a disturbance within the somatotropic axis. However, because the mutation did not co-segregate with the phenotype and functional characterization did not reveal an obvious impairment of the ligand depending major IGF1R signaling capabilities a second-site mutation was assumed. Mutational screening of components of the somatotropic axis, constituents of the IGF signaling system and factors involved in cellular proliferation, which are described or suggested to provoke syndromic dwarfism phenotypes, was performed. Two compound heterozygous PCNT mutations (p.[Arg585X];[Glu1774X]) were identified leading to the specification of the diagnosis to MOPD II. These investigations underline the need for careful assessment of all available information to derive a firm diagnosis from a sequence aberration.

Highlights

The process of human growth is an extraordinarily complex system with the somatotropic GH-IGF1 axis in the center of the endocrine regulation of pre- and postnatal growth
We report on a female patient with intrauterine growth retardation (IUGR) and severe postnatal growth failure carrying a novel IGF1R mutation and a compound heterozygous mutation in the pericentrin gene (PCNT) gene
Analysis of the IGF1R gene revealed a novel heterozygous variation (p.Leu1361Arg) that was subjected to further molecular characterization to assess its biochemical properties and cell-physiological effects

Summary

Introduction

The process of human growth is an extraordinarily complex system with the somatotropic GH-IGF1 axis in the center of the endocrine regulation of pre- and postnatal growth. Both microcephalic osteodysplastic primordal dwarfism type II (type Majewski or MOPD II, MIM 210720) [1,2] and mutations in the insulin-like growth factor 1 receptor gene (IGF1R, MIM 270450) are very rare causes of pre- and postnatal growth retardation. We report on a female patient with IUGR and severe postnatal growth failure carrying a novel IGF1R mutation and a compound heterozygous mutation in the PCNT gene. To assess the contribution of the IGF1R mutation to the phenotype of the patient in vitro studies examining the molecular consequences of the IGF1R mutation were performed

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