SEPN1: Associated with congenital fiber-type disproportion and insulin resistance

• Published in: Annals of neurology Vol. 59; no. 3; pp. 546 - 552
• Main Authors: Clarke, Nigel F., Kidson, Warren, Quijano-Roy, Susana, Estournet, Brigitte, Ferreiro, Ana, Guicheney, Pascale, Manson, James I., Kornberg, Andrew J., Shield, Lloyd K., North, Kathryn N.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-03-2006; Willey-Liss
• Subjects: Adenosine Triphosphatases - metabolism; Adolescent; Adult; Biological and medical sciences; Blotting, Western; Body Mass Index; Child; Diseases of striated muscles. Neuromuscular diseases; DNA Mutational Analysis - methods; Family Health; Female; Genetic Predisposition to Disease; Glucose Tolerance Test - methods; Human viral diseases; Humans; Infectious diseases; Insulin Resistance - genetics; Male; Medical sciences; Middle Aged; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myopathies, Structural, Congenital - genetics; Myopathies, Structural, Congenital - metabolism; Neurology; Selenoproteins - genetics; Selenoproteins - metabolism; Viral diseases; Viral diseases of the nervous system; Pancreatic hormone; Nervous system diseases; Congenital; Insulin
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.20761

Objective
Our first objective was to determine whether SEPN1 gene mutations are a cause of congenital fiber‐type disproportion (CFTD), a rare form of congenital myopathy in which relative hypotrophy of type 1 (slow twitch) muscle fibers is the principal abnormality on histology. Second, we investigated an association between SEPN1‐related myopathy and insulin resistance.
Methods
We sequenced SEPN1 in five unrelated CFTD patients with scoliosis and respiratory muscle weakness and screened an additional 22 CFTD patients for abnormalities in SEPN1 by Western blotting and restriction digest for the 943G→A mutation. We performed oral glucose tolerance tests (OGTTs) in eight SEPN1‐related myopathy patients.
Results
Two sisters with CFTD were homozygous for the 943G→A SEPN1 mutation and had clinical features typical of previously reported patients with SEPN1‐related myopathy. Five of eight SEPN1‐related myopathy patients had abnormalities on OGTT suggestive of insulin resistance.
Interpretation
SEPN1 is the second genetic cause of CFTD and the first cause of autosomal recessive CFTD to be identified to our knowledge. CFTD is the fourth clinicopathological presentation that can be associated with mutations in SEPN1. Insulin resistance may be a specific, previously unrecognized aspect of SEPN1‐related myopathy. Ann Neurol 2006