PUBLICATION
COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis
- Authors
- Rebello, D., Wohler, E., Erfani, V., Li, G., Aguilera, A.N., Santiago-Cornier, A., Zhao, S., Hwang, S.W., Steiner, R.D., Zhang, T.J., Gurnett, C.A., Raggio, C., Wu, N., Sobreira, N., Giampietro, P.F., Ciruna, B.
- ID
- ZDB-PUB-230719-38
- Date
- 2023
- Source
- Human molecular genetics 32(19): 2913-2928 (Journal)
- Registered Authors
- Ciruna, Brian, Gurnett, Christina
- Keywords
- none
- MeSH Terms
-
- Abnormalities, Multiple*/genetics
- Animals
- Collagen Type XI/genetics
- Humans
- Mutation, Missense
- Scoliosis*/genetics
- Spine/abnormalities
- Zebrafish/genetics
- PubMed
- 37462524 Full text @ Hum. Mol. Genet.
Citation
Rebello, D., Wohler, E., Erfani, V., Li, G., Aguilera, A.N., Santiago-Cornier, A., Zhao, S., Hwang, S.W., Steiner, R.D., Zhang, T.J., Gurnett, C.A., Raggio, C., Wu, N., Sobreira, N., Giampietro, P.F., Ciruna, B. (2023) COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis. Human molecular genetics. 32(19):2913-2928.
Abstract
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. The genetic cause for the vast majority of VMs are unknown. In a CS/VM patient cohort, three COL11A2 variants (R130W, R1407L, 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 LOF 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping