Open AccessNovel autosomal dominant TNNT 1 mutation causing nemaline myopathy
Author(s) -
Konersman Chamindra G.,
Freyermuth Fernande,
Winder Thomas L.,
Lawlor Michael W.,
LagierTourenne Clotilde,
Patel Shailendra B.
Publication year - 2017
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.325
Subject(s) - nemaline myopathy , proband , missense mutation , genetics , congenital myopathy , nonsense mutation , mutation , compound heterozygosity , sanger sequencing , biology , muscle biopsy , nebulin , myopathy , gene , medicine , sarcomere , titin , pathology , myocyte , biopsy , microbiology and biotechnology
Background Nemaline myopathy ( NEM ) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 ( TNNT 1 ) is 1 of 10 genes known to cause NEM . To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT 1 gene have been identified in NEM . This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder. Methods Proband and extended family underwent Sanger sequencing for TNNT 1 . We performed RT ‐ PCR and immunoblot on muscle to assess TNNT 1 RNA expression and protein levels in proband and father. Results We report a novel heterozygous missense mutation of TNNT 1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population. Conclusion This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM , but that this novel mutation likely acts via a dominant negative mechanism.