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Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia.
Eur J Hum Genet. 2019 03; 27(3):369-377.EJ

Abstract

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.

Authors+Show Affiliations

School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP, UK. Vitreoretinal Service, Addenbrooke's Hospital, Hills Road, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.East Anglian Medical Genetics Service, Box 134, Addenbrooke's Treatment Centre, Hills Road, Cambridge, CB2 0QQ, UK.East Anglian Medical Genetics Service, Box 134, Addenbrooke's Treatment Centre, Hills Road, Cambridge, CB2 0QQ, UK.Vitreoretinal Service, Addenbrooke's Hospital, Hills Road, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK.Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.East Anglian Medical Genetics Service, Box 134, Addenbrooke's Treatment Centre, Hills Road, Cambridge, CB2 0QQ, UK.School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0SP, UK. mps34@cam.ac.uk. Vitreoretinal Service, Addenbrooke's Hospital, Hills Road, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK. mps34@cam.ac.uk.

Pub Type(s)

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

Language

eng

PubMed ID

30568244

Citation

Nixon, Thomas R W., et al. "Bone Morphogenetic Protein 4 (BMP4) Loss-of-function Variant Associated With Autosomal Dominant Stickler Syndrome and Renal Dysplasia." European Journal of Human Genetics : EJHG, vol. 27, no. 3, 2019, pp. 369-377.
Nixon TRW, Richards A, Towns LK, et al. Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia. Eur J Hum Genet. 2019;27(3):369-377.
Nixon, T. R. W., Richards, A., Towns, L. K., Fuller, G., Abbs, S., Alexander, P., McNinch, A., Sandford, R. N., & Snead, M. P. (2019). Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia. European Journal of Human Genetics : EJHG, 27(3), 369-377. https://doi.org/10.1038/s41431-018-0316-y
Nixon TRW, et al. Bone Morphogenetic Protein 4 (BMP4) Loss-of-function Variant Associated With Autosomal Dominant Stickler Syndrome and Renal Dysplasia. Eur J Hum Genet. 2019;27(3):369-377. PubMed PMID: 30568244.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia. AU - Nixon,Thomas R W, AU - Richards,Allan, AU - Towns,Laura K, AU - Fuller,Gavin, AU - Abbs,Stephen, AU - Alexander,Philip, AU - McNinch,Annie, AU - Sandford,Richard N, AU - Snead,Martin P, Y1 - 2018/12/19/ PY - 2018/04/05/received PY - 2018/11/27/accepted PY - 2018/11/05/revised PY - 2018/12/21/pubmed PY - 2019/5/21/medline PY - 2018/12/21/entrez SP - 369 EP - 377 JF - European journal of human genetics : EJHG JO - Eur J Hum Genet VL - 27 IS - 3 N2 - Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition. SN - 1476-5438 UR - https://www.unboundmedicine.com/medline/citation/30568244/Bone_morphogenetic_protein_4__BMP4__loss_of_function_variant_associated_with_autosomal_dominant_Stickler_syndrome_and_renal_dysplasia_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30568244/ DB - PRIME DP - Unbound Medicine ER -