A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy

PloS One
Daniela RossiVincenzo Sorrentino

Abstract

A novel FLNC c.5161delG (p.Gly1722ValfsTer61) mutation was identified in two members of a French family affected by distal myopathy and in one healthy relative. This FLNC c.5161delG mutation is one nucleotide away from a previously reported FLNC mutation (c.5160delC) that was identified in patients and in asymptomatic carriers of three Bulgarian families with distal muscular dystrophy, indicating a low penetrance of the FLNC frameshift mutations. Given these similarities, we believe that the two FLNC mutations alone can be causative of distal myopathy without full penetrance. Moreover, comparative analysis of the clinical manifestations indicates that patients of the French family show an earlier onset and a complete segregation of the disease. As a possible explanation of this, the two French patients also carry a OBSCN c.13330C>T (p.Arg4444Trp) mutation. The p.Arg4444Trp variant is localized within the OBSCN Ig59 domain that, together with Ig58, binds to the ZIg9/ZIg10 domains of titin at Z-disks. Structural and functional studies indicate that this OBSCN p.Arg4444Trp mutation decreases titin binding by ~15-fold. On this line, we suggest that the combination of the OBSCN p.Arg4444Trp variant and of the FLNC c.5161delG mutatio...Continue Reading

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Citations

Jan 23, 2019·Protein Science : a Publication of the Protein Society·Jacob A WhitleyNathan T Wright
Feb 9, 2019·Muscle & Nerve·Stefano C PrevitaliMarina Mora
Mar 1, 2020·Human Mutation·Job A J VerdonschotHan G Brunner
Jul 3, 2019·Human Mutation·Vandana ShashiAikaterini Kontrogianni-Konstantopoulos
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Aug 14, 2018·Pflügers Archiv : European journal of physiology·Alyssa Grogan, Aikaterini Kontrogianni-Konstantopoulos
Jul 19, 2019·Proceedings of the National Academy of Sciences of the United States of America·Daniela RossiVincenzo Sorrentino
Apr 17, 2020·International Journal of Molecular Sciences·Zhenfeng Mao, Fumihiko Nakamura
Oct 15, 2020·Antioxidants·Judith Cantó-SantosGlòria Garrabou

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Datasets Mentioned

BETA
CAC44768.1

Methods Mentioned

BETA
exome sequencing
PCR
chip
NMR
X-ray
biopsy
biopsies
pull-down

Software Mentioned

Primer3
PolyPhen
COOT
PHENIX
PHENIX refine
YASARA
ImageJ
refine
Annovar
Ion Torrent Server

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