title: A novel nemaline myopathy in the Amish caused by a mutation in troponin T1.
abstract: The nemaline myopathies are characterized by weakness and eosinophilic, rodlike (nemaline) inclusions in muscle fibers. Amish nemaline myopathy is a form of nemaline myopathy common among the Old Order Amish. In the first months of life, affected infants have tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity develop before the children die of respiratory insufficiency, usually in the second year. The disorder has an incidence of approximately 1 in 500 among the Amish, and it is inherited in an autosomal recessive pattern. Using a genealogy database, automated pedigree software, and linkage analysis of DNA samples from four sibships, we identified an approximately 2-cM interval on chromosome 19q13.4 that was homozygous in all affected individuals. The gene for the sarcomeric thin-filament protein, slow skeletal muscle troponin T (TNNT1), maps to this interval and was sequenced. We identified a stop codon in exon 11, predicted to truncate the protein at amino acid 179, which segregates with the disease. We conclude that Amish nemaline myopathy is a distinct, heritable, myopathic disorder caused by a mutation in TNNT1.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA. jjohnsto@nhgri.nih.gov
authors.forename: J J
authors.initials: JJ
authors.lastname: Johnston
authors.forename: R I
authors.initials: RI
authors.lastname: Kelley
authors.forename: T O
authors.initials: TO
authors.lastname: Crawford
authors.forename: D H
authors.initials: DH
authors.lastname: Morton
authors.forename: R
authors.initials: R
authors.lastname: Agarwala
authors.forename: T
authors.initials: T
authors.lastname: Koch
authors.forename: A A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: C A
authors.initials: CA
authors.lastname: Francomano
authors.forename: L G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002835:Christianity; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D017696:Myopathies, Nemaline / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D020107:Troponin T / Q000737:chemistry / Q000235:genetics*
chemical_list: D020107:Troponin T