TY - JOUR
T1 - Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects
AU - University of Washington Center for Mendelian Genomics
AU - University of Washington Center for Rare Disease Research
AU - Chong, Jessica X.
AU - Childers, Matthew Carter
AU - Marvin, Colby T.
AU - Marcello, Anthony J.
AU - Gonorazky, Hernan
AU - Hazrati, Lili Naz
AU - Dowling, James J.
AU - Al Amrani, Fatema
AU - Alanay, Yasemin
AU - Nieto, Yolanda
AU - Gabriel, Miguel Á.Marín
AU - Aylsworth, Arthur S.
AU - Buckingham, Kati J.
AU - Shively, Kathryn M.
AU - Sommers, Olivia
AU - Anderson, Kailyn
AU - Regnier, Michael
AU - Bamshad, Michael J.
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/7/13
Y1 - 2023/7/13
N2 - Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7, TPM1, and TNNI3 that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes such as MYH2, TPM2, and TNNI2 that encode parts of the skeletal muscle sarcomere cause muscle diseases affecting skeletal muscle, such as distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., MYH7) encoding sarcomeric proteins in which the same pathogenic variant affects skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain pathogenic variants that also cause cardiac abnormalities. We report five families with DA because of heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 (ACTC1). ACTC1 encodes a highly conserved actin that binds to myosin in cardiac and skeletal muscle. Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition because of variants in ACTC1 and suggests that some functions of ACTC1 are shared in cardiac and skeletal muscle.
AB - Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7, TPM1, and TNNI3 that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes such as MYH2, TPM2, and TNNI2 that encode parts of the skeletal muscle sarcomere cause muscle diseases affecting skeletal muscle, such as distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., MYH7) encoding sarcomeric proteins in which the same pathogenic variant affects skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain pathogenic variants that also cause cardiac abnormalities. We report five families with DA because of heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 (ACTC1). ACTC1 encodes a highly conserved actin that binds to myosin in cardiac and skeletal muscle. Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition because of variants in ACTC1 and suggests that some functions of ACTC1 are shared in cardiac and skeletal muscle.
KW - cardiac defect
KW - cardiomyopathy
KW - congenital contractures
KW - distal arthrogryposis
KW - exome sequencing
KW - gene discovery
KW - Mendelian disease
KW - Mendelian disorder
KW - molecular dynamics simulations
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U2 - 10.1016/j.xhgg.2023.100213
DO - 10.1016/j.xhgg.2023.100213
M3 - Article
C2 - 37457373
AN - SCOPUS:85164271368
SN - 2666-2477
VL - 4
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 3
M1 - 100213
ER -