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

ABSTRACT: 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 DH5? 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.

SUBMITTER: Mustafa S

PROVIDER: S-EPMC7374443 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Mustafa Saima S Akhtar Zafrin Z Latif Muhammad M Hassan Mubashir M Faisal Muhammad M Iqbal Furhan F

Genes & genomics 20200606 8

<h4>Background</h4>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.<h4>Objective</h4>Present study was designed to report the molecular basis of AMDM in enrolled consanguineous family from Pakistan.<h4>Methods</h4>A consanguineous family from Vehari District in Pakistan having multiple siblings suffering from AMDM was enr ...[more]

PMID: 32506268

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Project description:Introduction: Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene have been reported to cause Acromesomelic Dysplasia, Maroteaux type 1 and short stature. While several hypotheses have been proposed to underlie the pathogenic mechanisms responsible for these conditions, the exact mechanisms, and functional characteristics of many of those variants and their correlations with the clinical manifestations have not been fully established. Methods: In this study, we examined eight NPR2 genetic missense variants (p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg318Gly, p.Arg388Gln, p.Arg495Cys, p.Arg557His, and p.Arg932Cys) Acromesomelic Dysplasia, Maroteaux type 1 and short stature located on diverse domains and broadly classified as variants of uncertain significance. The evaluated variants are either reported in patients with acromesomelic dysplasia in the homozygous state or short stature in the heterozygous state. Our investigation included the evaluation of their expression, subcellular trafficking and localization, N-glycosylation profiles, and cyclic guanosine monophosphate (cGMP) production activity. Results and Discussion: Our results indicate that variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg388Gln have defective cellular trafficking, being sequestered within the endoplasmic reticulum (ER), and consequently impaired cGMP production ability. Conversely, variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His seem to display a non-statistically significant behavior that is slightly comparable to WT-NPR2. On the other hand, p.Arg932Cys which is located within the guanylyl cyclase active site displayed normal cellular trafficking profile albeit with defective cGMP. Collectively, our data highlights the genotype-phenotype relationship that might be responsible for the milder symptoms observed in short stature compared to acromesomelic dysplasia. This study enhances our understanding of the functional consequences of several NPR2 variants, shedding light on their mechanisms and roles in related genetic disorders which might also help in their pathogenicity re-classification.

Project description:BackgroundIntimate Partner Violence (IPV) refers to behavior by an intimate partner that can cause physical, sexual, or psychological harm; is a common global public health issue requiring immediate attention. IPV is the most common form of violence in rural areas of Punjab, Pakistan.MethodsThis qualitative phenomenological study collected 46 in-depth interviews from married women who experienced IPV in the rural areas of South Punjab. A semi-structured interview guide was used for data collection. These women were selected through a snowball sampling technique from October 2018 to March 2019. Researchers accessed the study setting with the help of gatekeepers (Lady Health Workers and Village Heads). The interviews were audio-recorded in the local language (Saraiki) and were translated into English. The data were analyzed using the thematic inductive analysis technique.ResultsThe study has presented multifaceted factors of IPV by using the socio-ecological framework in rural areas of South Punjab, Pakistan. The current study introduced culturally contextualized terminologies of "protection," "physical submissiveness," "mental delicacy," and "social security". For married women, culturally embedded terms became the primary cause of IPV. In addition, the study also highlighted some of the cultural terminologies (such as run-mureed, watta-satta, beghairat, izzat, etc.) that are ubiquitous in the local context that sometimes intensifies IPV in the family and community sphere. Furthermore, the study discussed how gender-based inequalities trigger a status quo that ultimately creates power discrimination between spouses, which perpetuates violence in the domestic context.ConclusionsGender-prejudiced roles and expectations imposed by orthodoxy, misinterpretations of Islamic teachings, and dominant patriarchy can be contested through awareness campaigns among the public, and gender sensitization drives among public institutions of police and judiciary. Education and employment-based can lead to women's empowerment and help to challenge the orthodox anti-feminist societal norms and the role of kinship-based networks in the family and community sphere.

Dataset Information

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

Publications

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

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