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GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment

Multiple synostoses syndrome type 4 (SYNS4; MIM 617898) is an autosomal dominant disorder characterized by carpal-tarsal coalition and otosclerosis-associated hearing loss. SYSN4 has been associated with GDF6 gain-of-function mutations. Here we report a five-generation SYNS4 family with a reduction...

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Autores principales: Clarke, Raymond A., Fang, Zhiming, Murrell, Dedee, Sheriff, Tabrez, Eapen, Valsamma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470939/
https://www.ncbi.nlm.nih.gov/pubmed/34573339
http://dx.doi.org/10.3390/genes12091354
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author Clarke, Raymond A.
Fang, Zhiming
Murrell, Dedee
Sheriff, Tabrez
Eapen, Valsamma
author_facet Clarke, Raymond A.
Fang, Zhiming
Murrell, Dedee
Sheriff, Tabrez
Eapen, Valsamma
author_sort Clarke, Raymond A.
collection PubMed
description Multiple synostoses syndrome type 4 (SYNS4; MIM 617898) is an autosomal dominant disorder characterized by carpal-tarsal coalition and otosclerosis-associated hearing loss. SYSN4 has been associated with GDF6 gain-of-function mutations. Here we report a five-generation SYNS4 family with a reduction in GDF6 expression resulting from a chromosomal breakpoint 3′ of GDF6. A 30-year medical history of the family indicated bilateral carpal-tarsal coalition in ~50% of affected family members and acquired otosclerosis-associated hearing loss in females only, whereas vertebral fusion was present in all affected family members, most of whom were speech impaired. All vertebral fusions were acquired postnatally in progressive fashion from a very early age. Thinning across the 2nd cervical vertebral interspace (C2-3) in the proband during infancy progressed to block fusion across C2-7 and T3-7 later in life. Carpal-tarsal coalition and pisiform expansion were bilaterally symmetrical within, but varied greatly between, affected family members. This is the first report of SYNS4 in a family with reduced GDF6 expression indicating a prenatal role for GDF6 in regulating development of the joints of the carpals and tarsals, the pisiform, ears, larynx, mouth and face and an overlapping postnatal role in suppression of aberrant ossification and synostosis of the joints of the inner ear (otosclerosis), larynx and vertebrae. RNAseq gene expression analysis indicated >10 fold knockdown of NOMO3, RBMXL1 and NEIL2 in both primary fibroblast cultures and fresh white blood cells. Together these results provide greater insight into the role of GDF6 in skeletal joint development.
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spelling pubmed-84709392021-09-27 GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment Clarke, Raymond A. Fang, Zhiming Murrell, Dedee Sheriff, Tabrez Eapen, Valsamma Genes (Basel) Article Multiple synostoses syndrome type 4 (SYNS4; MIM 617898) is an autosomal dominant disorder characterized by carpal-tarsal coalition and otosclerosis-associated hearing loss. SYSN4 has been associated with GDF6 gain-of-function mutations. Here we report a five-generation SYNS4 family with a reduction in GDF6 expression resulting from a chromosomal breakpoint 3′ of GDF6. A 30-year medical history of the family indicated bilateral carpal-tarsal coalition in ~50% of affected family members and acquired otosclerosis-associated hearing loss in females only, whereas vertebral fusion was present in all affected family members, most of whom were speech impaired. All vertebral fusions were acquired postnatally in progressive fashion from a very early age. Thinning across the 2nd cervical vertebral interspace (C2-3) in the proband during infancy progressed to block fusion across C2-7 and T3-7 later in life. Carpal-tarsal coalition and pisiform expansion were bilaterally symmetrical within, but varied greatly between, affected family members. This is the first report of SYNS4 in a family with reduced GDF6 expression indicating a prenatal role for GDF6 in regulating development of the joints of the carpals and tarsals, the pisiform, ears, larynx, mouth and face and an overlapping postnatal role in suppression of aberrant ossification and synostosis of the joints of the inner ear (otosclerosis), larynx and vertebrae. RNAseq gene expression analysis indicated >10 fold knockdown of NOMO3, RBMXL1 and NEIL2 in both primary fibroblast cultures and fresh white blood cells. Together these results provide greater insight into the role of GDF6 in skeletal joint development. MDPI 2021-08-29 /pmc/articles/PMC8470939/ /pubmed/34573339 http://dx.doi.org/10.3390/genes12091354 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Clarke, Raymond A.
Fang, Zhiming
Murrell, Dedee
Sheriff, Tabrez
Eapen, Valsamma
GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment
title GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment
title_full GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment
title_fullStr GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment
title_full_unstemmed GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment
title_short GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment
title_sort gdf6 knockdown in a family with multiple synostosis syndrome and speech impairment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470939/
https://www.ncbi.nlm.nih.gov/pubmed/34573339
http://dx.doi.org/10.3390/genes12091354
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