TNNI1 Mutated in Autosomal Dominant Proximal Arthrogryposis

Case Presentation

A 14-year-old boy presented with contractures of the trunk, hip, and knee joints. The family had an apparent autosomal dominant family history of joint contractures and high creatine kinase affecting the father and paternal grandfather, albeit without muscle weakness (Figure, A). The proband was born with clasped thumbs, inguinal hernia, and testicular hydrocele, which were corrected by surgery at age 5 months. At elementary school ages, he noticed difficulties with jumping, sitting with his legs crossed, and bending his back. At age 14 years, he visited the hospital seeking medical workup for contractures. On examination, his height and weight were 153 cm (−2.1 SD) and 41.4 kg (−1.5 SD), respectively. He had small mouth and trismus. He had no apparent muscle weakness but had joint contractures of the neck, trunk, and knees. The serum creatine kinase level was 1,689 IU/L (normal range: 25–170 IU/L). No edematous change or fat replacement was observed on muscle MRI. Muscle biopsy from the left biceps brachii demonstrated mild disorganization of the intermyofibrillar network, showing a moth-eaten appearance in some type 1 fibers and mild fiber size variation in the type 1 fibers. The minimum Feret diameters of type 1 fibers were marginally larger than those of type 2 fibers in patient III-2. Electron microscopic analysis revealed that type 1 fibers, identified by the Z-band width, had Z disk streaming (Figure, B).

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Figure Pedigree and Pathologic and Genetic Findings

(A) Pedigree of a Japanese arthrogryposis family. (B) Skeletal muscle pathology of patient III-2. (Upper left) NADHTR staining shows fibers with moth-eaten appearance. (Upper right) Myosin ATPase staining with pH 4.6 preincubation demonstrates type 1 fibers. Bar denotes 20 microns. (Lower left) The minimum Feret diameters of type 1 fibers were marginally larger than those of type 2 fibers in patient III-2. (Lower right) Electron microscopic analysis: Z disk streaming was observed in type 1 muscle fibers, with the average width of Z bands of the fibers with Z disk streaming at 95 nm. Bar denotes 5.0 microns. (C) (Left) Electropherograms of genomic DNAs in the family. c.523A>T was identified in patients II-1 and III-2 but not in patient III-1. (Right) Transcript with c.523A>T of TNNI1 in the patient's skeletal muscle. (D) Schematic structure of troponin I1 consists of 6 α-helices and position of the identified nonsense variant at 175. ID, inhibitory domain; RD, regulatory domain. Lysine residue at 175 in troponin I1 is highly conserved within the C-terminus. The 11 TNNI2 pathogenic variants reported in patients with distal arthrogryposis are indicated at the bottom. Tropomyosin-binding site is indicated by a rectangle. Green letters, missense; blue letters, deletion; red letters, nonsense variant.

To genetically diagnose the proband, we performed pathogenic variant screening using a custom-made targeted gene panel for inherited skeletal muscle diseases, which revealed no pathogenic variant. Trio-based exome sequencing (II-1, III-1, and III-2) identified a heterozygous nonsense variant, c.523A>T (p.K175*), in TNNI1 (NM_003281.4), which was confirmed by Sanger sequencing (Figure, C). The nonsense variant was segregated among II-1, III-1, and III-2. In addition, the reverse transcription–PCR products of mRNA from the patient's muscle showed the presence of both the mutated and normal transcripts. The altered amino acid residue (p.K175) is within the tropomyosin-binding site near the C-terminus, which is highly conserved in the troponin family and is evolutionarily conserved.¹ This variant is not registered in any public databases, including gnomAD, dbSNP151, HGMD Professional 2021.1, Human Genome Variation Database, ToMMo, ClinVar, ESP6500, and 1000 Genomes.

Study Funding

This study was supported partly by Intramural Research Grants (2-5 and 30-9) for Neurological and Psychiatric Disorders of NCNP and by AMED under Grant Number 20ek0109490h0001.

Disclosure

Y. Nishimori reports no disclosures relevant to the manuscript. A. Iida received grants from Intramural Research Grants (2-5 and 30-9) for Neurological and Psychiatric Disorders of NCNP and AMED under Grant Numbers 20ek0109490h0001 and Joint Usage and Joint Research Programs, the Institute of Advanced Medical Sciences, Tokushima University grant number 2020, 2A19. M. Ogasawara, M. Okubo, Y. Yonenobu, M. Kinoshita, and K. Sugie report no disclosures relevant to the manuscript. S. Noguchi received grants from Intramural Research Grants (2-6 and 3-9) for Neurological and Psychiatric Disorders of NCNP and AMED under Grant Number 20ek0109490h0001. I. Nishino received a grant from Intramural Research Grant (2-5) for Neurological and Psychiatric Disorders of NCNP and AMED under Grant Number 20ek0109490h0001. Go to Neurology.org/NG for full disclosures.