Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8321890 | The International Journal of Biochemistry & Cell Biology | 2018 | 11 Pages |
Abstract
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.(Leu314âArg), 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.(Leu314âArg)] in family A allosterically affects binding of NPR2 homodimer to its ligand (CNP) which ultimately results in defective guanylate cyclase activity. A nonsense mutation [p.(Arg371*)] in family B entirely removed the transmembrane domain, protein kinase domain and guanylate cyclase domains of the NPR2 resulting in abolishing its guanylate cyclase activity. Another novel mutation [p.(Arg1032*)], found in family C, deteriorated the guanylate cyclase domain of the protein and probably plundered its guanylate cyclase activity. These results suggest that guanylate cyclase activity is the most critical function of the NPR2 and phenotypic severity of the NPR2 mutations is proportional to the reduction in its guanylate cyclase activity.
Keywords
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Authors
Irfanullah Irfanullah, Amir Zeb, Naila Shinwari, Khadim Shah, Syed Zohaib Tayyab Gilani, Saadullah Khan, Keun Woo Lee, Syed Irfan Raza, Shabir Hussain, Khurram Liaqat, Wasim Ahmad,