Homozygous Sequence Variants in the <i>NPR2</i> Gene Underlying Acromesomelic Dysplasia Maroteaux Type (AMDM) in Consanguineous Families

Khan

American J of Med Genetics Pt A

et al. 2016

Self Cite

Postaxial polydactyly (PAP) is one of the most common congenital malformations observed in the general population. However, it can also occur as part of a syndrome. Unbiased genetic screening techniques such as exome sequencing are highly appropriate methods to provide a molecular diagnosis in patients with polydactyly due to the large number of mutated genes associated with it. The present study describes a consanguineous family of Pakistani origin with PAP, speech impairment, hearing impairment of variable degree, and proportionate short stature with no prominent intellectual disability or ophthalmological abnormalities. One affected individual of the family was subjected to exome sequencing which resulted in the identification of four homozygous variants including an in-frame deletion (c.1115_1117delCCT; p.(Ser372del) in MKS1, which was later shown to be the only variant segregating with the phenotype. In silico predictions supported the potential pathogenicity of the identified mutation. Additional clinical tests and MRI features of a patient in the family showed a molar tooth sign, which is a hallmark of Joubert syndrome. In conclusion, we have described a pathogenic variant in the MKS1 resulting in a mild Joubert syndrome phenotype, which broadens the spectrum of mutations in the MKS1. © 2016 Wiley Periodicals, Inc.

Section: Methodsmentioning

confidence: 99%

Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1‐related ciliopathies

Khan

American J of Med Genetics Pt A

et al. 2016

Self Cite

“…In humans, overexpression of CNP results in overgrowth [42, 43]. Conversely, homozygous inactivating mutations in natriuretic peptide receptor 2 ( NPR2 ), the primary receptor for CNP, cause acromesomelic dysplasia, Maroteaux type [44], whereas heterozygous mutations can present as idiopathic short stature with no or only subtle signs of a skeletal dysplasia [45, 46]. In 2 recent studies of idiopathic short stature, cohorts identified heterozygous NPR2 mutations in 0–6% of the patients [47, 48].…”

Section: Molecular Mechanism Involved In Longitudinal Growthmentioning

confidence: 99%

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

2017

Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.

“…Acromesomelic dysplasias is a pathological condition during development during which skeletal elements under goes disproportionate shortening and usually middle parts of the forearms and legs are more affected (Bartels et al 2004 ; Irfanullah et al 2015 ). Acromesomelic dysplasia has three reported sub types based on phenotypic and radiological variations recorded in the patients: type Grebe (AMDG) (MIM #200700) (Umair et al 2016 ), type Hunter and Thompson (AMDH) (MIM #201250) (Ullah et al 2018 ) and Maroteaux type (AMDM) (MIM #602875) (Bartels et al 2004 ).…”

Section: Introductionmentioning

confidence: 99%

A novel nonsense mutation in NPR2 gene causing Acromesomelic dysplasia, type Maroteaux in a consanguineous family in Southern Punjab (Pakistan)

et al. 2020

Background Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare skeletal dysplasia following autosomal recessive mode of inheritance and characterized by abnormal growth plates, short and abnormal bones in the extremities and spine. Objective Present study was designed to report the molecular basis of AMDM in enrolled consanguineous family from Pakistan. Methods A consanguineous family from Vehari District in Pakistan having multiple siblings suffering from AMDM was enrolled in present study. Whole exome sequencing (WES) approach was adopted to identify causative agent of AMDM. Human full length NPR2 gene and sequence with nonsense mutation was amplified by using Myc-tagged pXN vector and transformed in E. coli DH5α cells to confirm mutation. SDS-PAGE and Western blotting were done to confirm the production of truncated protein. Computational three dimensional structure generation through homology modeling approach was done to compare protein structure between patients and controls. Results WES reveled a nonsense mutation (c.613 C>T, p.R205X) in exon 1 of NPR2 gene leading to premature termination codon in mRNA of NPR2 gene resulting in a truncated protein with 204 amino acid residues that was confirmed by SDS-PAGE and Western blotting. Sanger sequencing confirmed that mutation in all subjects and mutation followed Mendalian pattern of inheritance. Multiple sequence alignment by ClustalW revealed that mutated domain of NPR2 is conserved region. Proetin structure comparison revealed a significant structural part of NPR2 was missing in truncated protein as compared to control. Conclusion We are reporting that a novel nonsense mutation (c.613 C>T, p.R205X) in exon 1 of NPR2 gene is causing AMDM in a consanguineous Pakistani family.