Skip to Content
Merck
  • A new titinopathy: Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy.

A new titinopathy: Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy.

Neurology (2015-11-20)
Rafael De Cid, Rabah Ben Yaou, Carinne Roudaut, Karine Charton, Sylvain Baulande, France Leturcq, Norma Beatriz Romero, Edoardo Malfatti, Maud Beuvin, Anna Vihola, Audrey Criqui, Isabelle Nelson, Juliette Nectoux, Laurène Ben Aim, Christophe Caloustian, Robert Olaso, Bjarne Udd, Gisèle Bonne, Bruno Eymard, Isabelle Richard
ABSTRACT

To identify the genetic defects present in 3 families with muscular dystrophy, contractures, and calpain 3 deficiency. We performed targeted exome sequencing on one patient presenting a deficiency in calpain 3 on Western blot but for which mutations in the gene had been excluded. The identification of a homozygous truncating mutation in the M-line part of titin prompted us to sequence this region in 2 additional patients presenting similar clinical and biochemical characteristics. The 3 patients shared similar features: coexistence of limb-girdle weakness and early-onset diffuse joint contractures without cardiomyopathy. The biopsies showed rimmed vacuoles, a dystrophic pattern, and secondary reduction in calpain 3. We identified a novel homozygous mutation in the exon Mex3 of the TTN gene in the first patient. At protein level, this mutation introduces a stop codon at the level of Mex3. Interestingly, we identified truncating mutations in both alleles in the same region of the TTN gene in patients from 2 additional families. Molecular protein analyses confirm loss of the C-ter part of titin. Our study broadens the phenotype of titinopathies with the report of a new clinical entity with prominent contractures and no cardiac abnormality and where the recessive mutations lead to truncation of the M-line titin and secondary calpain 3 deficiency.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Titin Antibody, clone 9B9, culture supernatant, clone 9B9, Chemicon®
Sigma-Aldrich
Monoclonal Anti-α-Actinin (Sarcomeric) antibody produced in mouse, clone EA-53, ascites fluid