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A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures.
Gene 2013; 527(2):630-5GENE

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+Show Affiliations

Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23850728

Citation

Li, Xuefu, et al. "A Novel TNNI2 Mutation Causes Freeman-Sheldon Syndrome in a Chinese Family With an Affected Adult With Only Facial Contractures." Gene, vol. 527, no. 2, 2013, pp. 630-5.
Li X, Jiang M, Han W, et al. A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures. Gene. 2013;527(2):630-5.
Li, X., Jiang, M., Han, W., Zhao, N., Liu, W., Sui, Y., ... Li, J. (2013). A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures. Gene, 527(2), pp. 630-5. doi:10.1016/j.gene.2013.06.082.
Li X, et al. A Novel TNNI2 Mutation Causes Freeman-Sheldon Syndrome in a Chinese Family With an Affected Adult With Only Facial Contractures. Gene. 2013 Sep 25;527(2):630-5. PubMed PMID: 23850728.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel TNNI2 mutation causes Freeman-Sheldon syndrome in a Chinese family with an affected adult with only facial contractures. AU - Li,Xuefu, AU - Jiang,Miao, AU - Han,Weitian, AU - Zhao,Ning, AU - Liu,Wei, AU - Sui,Yu, AU - Lu,Yongping, AU - Li,Jianxin, Y1 - 2013/07/11/ PY - 2013/04/11/received PY - 2013/06/24/revised PY - 2013/06/27/accepted PY - 2013/7/16/entrez PY - 2013/7/16/pubmed PY - 2013/10/31/medline KW - A KW - DA KW - DA1 (2B/2A) KW - DAs KW - Distal arthrogryposis KW - FSS KW - Freeman–Sheldon syndrome KW - MYBPC1 KW - MYH3 KW - Mutation KW - PAGE KW - RFLP KW - SHS KW - Sheldon–Hall syndrome KW - Somatic mosaicism KW - T KW - TNNI2 KW - TNNT3 KW - TPM2 KW - adenosine KW - base pair(s) KW - bp KW - distal arthrogryposes KW - distal arthrogryposis KW - distal arthrogryposis type 1 (2B/2A) KW - homo sapiens embryonic myosin heavy chain 3 gene KW - homo sapiens myosin binding protein C slow type gene KW - homo sapiens tropomyosin 2 gene KW - homo sapiens troponin I type 2 gene KW - homo sapiens troponin T type 3 gene KW - polyacrylamide gel electrophoresis KW - restriction fragment length polymorphism KW - thymidine SP - 630 EP - 5 JF - Gene JO - Gene VL - 527 IS - 2 N2 - 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. SN - 1879-0038 UR - https://www.unboundmedicine.com/medline/citation/23850728/A_novel_TNNI2_mutation_causes_Freeman_Sheldon_syndrome_in_a_Chinese_family_with_an_affected_adult_with_only_facial_contractures_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-1119(13)00850-0 DB - PRIME DP - Unbound Medicine ER -