title: A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures.
abstract: Distal arthrogryposes (DAs), a clinically and genetically heterogeneous group of disorders characterized by congenital contractures with predominant involvement of the hands and feet, can be classified into at least 12 different forms. These autosomal dominant disorders are of variable expressivity and reduced penetrance. Mutations in sarcomeric protein genes, including troponin I2 (TNNI2), troponin T3 (TNNT3), tropomyosin 2 (TPM2), embryonic myosin heavy chain 3 (MYH3), and myosin binding protein C1 (MYBPC1), have been identified in distal arthrogryposis type 1 (DA1, MIM 108120), type 2B (DA2B, MIM 601680) and type 2A (DA2A)/Freeman-Sheldon syndrome (FSS, MIM 193700). However, mutations causing FSS have only been reported in MYH3. Herein we describe a Chinese DA family whose members meet classical strict criteria for FSS, as well as one member of the family who has isolated facial features consistent with FSS. No disease-causing mutation was found in MYH3. Segregation of microsatellite markers flanking the TNNI2 and TNNT3 genes at 11p15.5 was compatible with linkage. Subsequent sequencing of TNNI2 revealed a novel mutation, c.A493T (p.I165F), located in the C-terminal region, which is critical for proper protein function. This mutation was found to cosegregate with the FSS phenotype in this family, and assessment using SIFT and PolyPhen-2 predicted a damaging effect. To the best of our knowledge, we report the first TNNI2 mutation in classical FSS and describe an atypical adult FSS case with only facial contractures resulting from somatic mosaicism. We infer that DA1, DA2B and FSS represent a phenotypic continuum of the same disorder and provide further genetic evidence for this hypothesis.
authors.affiliation: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors.forename: Xuefu
authors.initials: X
authors.lastname: Li
authors.forename: Miao
authors.initials: M
authors.lastname: Jiang
authors.forename: Weitian
authors.initials: W
authors.lastname: Han
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Sui
authors.forename: Yongping
authors.initials: Y
authors.lastname: Lu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
mesh_terms: D000328:Adult; D002681:China; D002874:Chromosome Mapping; D003286:Contracture / Q000235:genetics*; D003394:Craniofacial Dysostosis / Q000235:genetics*; D005145:Face; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D019210:Troponin I / Q000235:genetics*
chemical_list: C518658:TNNI2 protein, human; D019210:Troponin I
keywords: A; DA; DA1 (2B/2A); DAs; Distal arthrogryposis; FSS; Freeman–Sheldon syndrome; MYBPC1; MYH3; Mutation; PAGE; RFLP; SHS; Sheldon–Hall syndrome; Somatic mosaicism; T; TNNI2; TNNT3; TPM2; adenosine; base pair(s); bp; distal arthrogryposes; distal arthrogryposis; distal arthrogryposis type 1 (2B/2A); homo sapiens embryonic myosin heavy chain 3 gene; homo sapiens myosin binding protein C slow type gene; homo sapiens tropomyosin 2 gene; homo sapiens troponin I type 2 gene; homo sapiens troponin T type 3 gene; polyacrylamide gel electrophoresis; restriction fragment length polymorphism; thymidine