scholarly journals A role for the MEGF6 gene in predisposition to osteoporosis

2020 ◽  
Author(s):  
Craig C. Teerlink ◽  
Michael J Jurynec ◽  
Rolando Hernandez ◽  
Jeff Stevens ◽  
Dana C. Hughes ◽  
...  

ABSTRACTOsteoporosis is a common skeletal disorder characterized by deterioration of bone tissue in later life. The set of genetic factors contributing to osteoporosis is not completely specified. High-risk osteoporosis pedigrees were analyzed to identify genes that may confer susceptibility to disease. Candidate predisposition variants were identified initially by whole exome sequencing of affected-relative-pairs, approximately cousins, from ten pedigrees. Variants were filtered on the basis of population frequency, concordance between pairs of cousins, affecting a gene associated with osteoporosis, and likelihood to have functionally damaging, pathogenic consequences. Subsequently variants were tested for segregation in 68 additional relatives of the index carriers. A rare variant in MEGF6 (rs755467862) showed strong evidence of segregation with the disease phenotype. Predicted protein folding indicated the variant (Cys200Tyr) may disrupt structure of an EGF-like calcium-binding domain of MEGF6. Functional analyses demonstrated that complete loss of the paralogous genes megf6a and megf6b in zebrafish resulted in significant delay of cartilage and bone formation. Segregation analyses, in-silico protein structure modeling, and functional assays support a role for MEGF6 in predisposition to osteoporosis.

2007 ◽  
Vol 23 (19) ◽  
pp. 2558-2565 ◽  
Author(s):  
N. Fernandez-Fuentes ◽  
B. K. Rai ◽  
C. J. Madrid-Aliste ◽  
J. Eduardo Fajardo ◽  
A. Fiser

2010 ◽  
Vol 38 (Web Server) ◽  
pp. W569-W575 ◽  
Author(s):  
F. Lauck ◽  
C. A. Smith ◽  
G. F. Friedland ◽  
E. L. Humphris ◽  
T. Kortemme

2005 ◽  
Vol 33 (Web Server) ◽  
pp. W111-W115 ◽  
Author(s):  
A. Zemla ◽  
C. E. Zhou ◽  
T. Slezak ◽  
T. Kuczmarski ◽  
D. Rama ◽  
...  

Author(s):  
Narayanan Eswar ◽  
David Eramian ◽  
Ben Webb ◽  
Min-Yi Shen ◽  
Andrej Sali

2020 ◽  
Author(s):  
denglu yan ◽  
zhaojie Wang ◽  
Zhi Zhang

Abstract Background: The aim of this study was to identify genetic factors and chromosomal regions contributing to osteonecrosis of the femoral head (ONFH) in a Chinese family with presentations of Legg-Calvé-Perthes Disease (LCDP). Methods: In this study, we performed whole exon sequencing of a Chinese family with LCPD for mutation detection. Ten members had ONFH in twenty-seven family members in four generations family, 5 unaffected members of the studied family and 5 normal peoples as control were underwent whole exome sequencing for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution. Results: In this Chinese family affected by LCPD, the mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain was present in 10 patients but absent in 5 unaffected members of the studied family and in 5 control chromosomes from unaffected individuals of matched geographical ancestry. The COL2A1 gene mutation was further validated by Sanger sequencing, confirmed that were heterozygous for the mutation. Then, we identified the p.Gly1170Ser mutation in exon 50 of COL2A1 in a Chinese family with LCPD. Conclusions: This study maps the mutation of mutation (c.3508 G>A, p. Gly1170Ser) in exon 50 of COL2A1 in the Gly–X–Y domain in a Chinese family of LCPD, which causes osteonecrosis of femoral head.


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