TNNI1 Mutated in Autosomal Dominant Proximal Arthrogryposis

Abstract

ObjectivesThe main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis.MethodsWe performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing.ResultsA 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in TNNI1 in the family.DiscussionThe altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with TNNI2 variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a TNNI1 nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of TNNI1 in the disease.

Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease

“…This interpretation is consistent with the reduction in the fractional positive charge affected by the cTnI variants p.K178E and p.R192H, resulting in substantial increases in calcium sensitivity in skinned fiber preparations ( 35 ). The previously reported p.K175* TNNI1 variant resulting in a hypercontractile phenotype was shown to escape nonsense-mediated decay, with a truncated transcript identified in patient muscle ( 3 ). This variant is flanked by the gain-of-function variants reported here (p.R174Q and p.K176del), suggesting that its pathomechanism is also associated with a reduction in the fractional positively charged amino acid content.…”

“…Our data would also support the hypothesis postulated by Nishimori et al . ( 3 ), who suspected that an increased Ca 2+ sensitivity of force was the underlying disease mechanism of a presumed gain-of-function c.523A>T, p.K175* TNNI1 variant in a family with arthrogryposis and elevated CK.…”

“…Genes encoding the Tn isoforms have been implicated in congenital (cardio)myopathies reviewed in ( 2 ), with the single exception of the gene encoding the slow skeletal TnI isoform [ssTnI; TNNI1 ; Online Mendelian Inheritance in Man (OMIM): 191042] ( 2 ). TNNI1 was only recently tentatively implicated in myopathy in a single family with dominant proximal arthrogryposis, although the pathogenicity of the reported TnI variant (p.K175*) was not further investigated ( 3 ). ssTnI is predominantly expressed in fetal heart and slow-twitch skeletal myofibers ( 4 , 5 ), whereas fast skeletal TnI ( TNNI2 ) is expressed in fast-twitch skeletal myofibers and cTnI ( TNNI3 ) is expressed in cardiac muscle.…”