COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis.

Autor:	Rebello D; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.; Department of Molecular Genetics, The University of Toronto, Toronto, Ontario M5S 1A8, Canada., Wohler E; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Erfani V; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.; Department of Molecular Genetics, The University of Toronto, Toronto, Ontario M5S 1A8, Canada., Li G; Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China., Aguilera AN; Department of Pediatrics, University of Illinois-Chicago, Chicago, IL 60612, USA., Santiago-Cornier A; Genetic Section, San Jorge Children's and Women's Hospital, San Juan, Puerto Rico 00912, USA.; Department of Public Health, Ponce Health Sciences University, Ponce, Puerto Rico 00912, USA., Zhao S; Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Hwang SW; Shriners Children's-Philadelphia, Philadelphia, PA 19140, USA., Steiner RD; Department of Pediatrics, University of Wisconsin, Madison, WI 54449, USA.; Marshfield Clinic Health System, Marshfield, WI 54449, USA., Zhang TJ; Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China., Gurnett CA; Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA., Raggio C; Hospital for Special Surgery, New York, NY 10021, USA., Wu N; Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China., Sobreira N; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Giampietro PF; Department of Pediatrics, University of Illinois-Chicago, Chicago, IL 60612, USA., Ciruna B; Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.; Department of Molecular Genetics, The University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2023 Sep 16; Vol. 32 (19), pp. 2913-2928.
DOI:	10.1093/hmg/ddad117
Abstrakt:	Human vertebral malformations (VMs) have an estimated incidence of 1/2000 and are associated with significant health problems including congenital scoliosis (CS) and recurrent organ system malformation syndromes such as VACTERL (vertebral anomalies; anal abnormalities; cardiac abnormalities; tracheo-esophageal fistula; renal anomalies; limb anomalies). The genetic cause for the vast majority of VMs are unknown. In a CS/VM patient cohort, three COL11A2 variants (R130W, R1407L and R1413H) were identified in two patients with cervical VM. A third patient with a T9 hemivertebra and the R130W variant was identified from a separate study. These substitutions are predicted to be damaging to protein function, and R130 and R1407 residues are conserved in zebrafish Col11a2. To determine the role for COL11A2 in vertebral development, CRISPR/Cas9 was used to create a nonsense mutation (col11a2L642*) as well as a full gene locus deletion (col11a2del) in zebrafish. Both col11a2L642*/L642* and col11a2del/del mutant zebrafish exhibit vertebral fusions in the caudal spine, which form due to mineralization across intervertebral segments. To determine the functional consequence of VM-associated variants, we assayed their ability to suppress col11a2del VM phenotypes following transgenic expression within the developing spine. While wildtype col11a2 expression suppresses fusions in col11a2del/+ and col11a2del/del backgrounds, patient missense variant-bearing col11a2 failed to rescue the loss-of-function phenotype in these animals. These results highlight an essential role for COL11A2 in vertebral development and support a pathogenic role for two missense variants in CS. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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