Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of Acromesomelic dysplasia, type Maroteaux

The International Journal of Biochemistry & Cell Biology
IrfanullahWasim Ahmad

Abstract

Homozygous and/or heterozygous loss of function mutations in the natriuretic peptide receptor B (NPR2) have been reported in causing acromesomelic dysplasia, type Maroteaux with variable clinical features and idiopathic short stature with nonspecific skeletal deformities. On the other hand, gain of function mutations in the same gene result in overgrowth disorder suggesting that NPR2 and its ligand, natriuretic peptide precursor C (CNP), are the key players of endochondral bone growth. However, the precise mechanism behind phenotypic variability of the NPR2 mutations is not fully understood so far. In the present study, three consanguineous families of Pakistani origin (A, B, C) with variable phenotypes of acromesomelic dysplasia, type Maroteaux were evaluated at clinical and molecular levels. Linkage analysis followed by Sanger sequencing of the NPR2 gene revealed three homozygous mutations including p.(Leu314 Arg), p.(Arg371*), and p.(Arg1032*) in family A, B and C, respectively. In silico structural and functional analyses substantiated that a novel missense mutation [p.(Leu314 Arg)] in family A allosterically affects binding of NPR2 homodimer to its ligand (CNP) which ultimately results in defective guanylate cyclase activi...Continue Reading

Citations

Jan 22, 2020·Molecular Genetics & Genomic Medicine·Il Tae HwangMin Jae Kang
Jan 29, 2020·The Journal of Clinical Endocrinology and Metabolism·Lukas PlachyStepanka Pruhova
Nov 19, 2020·The Journal of Clinical Endocrinology and Metabolism·Xiaoan KeHuijuan Zhu
Jun 24, 2021·Journal of Pediatric Endocrinology & Metabolism : JPEM·Esra KılıçMustafa Kılıç

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