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TNNI1 Mutated in Autosomal Dominant Proximal Arthrogryposis
Yukako Nishimori1, Aritoshi Iida1, Masashi Ogasawara1
1Department of Neuromuscular Research (Y.N., M.O., M.O., S.N., I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan; Department of Clinical Genome Analysis, Medical Genome Center, NCNP, Tokyo, Japan (Y.N., A.I., I.N.); Department of Neurology (Y.N., K.S.), Nara Medical University, Nara, Japan; Department of Neurology (Y.Y., M.K.), Osaka University Graduate School of Medicine, Osaka, Japan.
Objectives:
The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis.
Methods:
We performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing.
Results:
A 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.
Discussion:
The 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.
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