Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family

Abstract Idiopathic scoliosis (IS) is a complex 3D deformation of the spine with a strong genetic component, most commonly found in adolescent girls. Adolescent idiopathic scoliosis (AIS) affects around 3% of the general population. In a 5-generation UK family, linkage analysis identified the locus...

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Autores principales:	Hélène Mathieu, Shunmoogum A. Patten, Jose Antonio Aragon-Martin, Louise Ocaka, Michael Simpson, Anne Child, Florina Moldovan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2c82ae51ab604986949fc32ba08186ed
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spelling	oai:doaj.org-article:2c82ae51ab604986949fc32ba08186ed2021-12-02T15:00:20ZGenetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family10.1038/s41598-021-90155-02045-2322https://doaj.org/article/2c82ae51ab604986949fc32ba08186ed2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90155-0https://doaj.org/toc/2045-2322Abstract Idiopathic scoliosis (IS) is a complex 3D deformation of the spine with a strong genetic component, most commonly found in adolescent girls. Adolescent idiopathic scoliosis (AIS) affects around 3% of the general population. In a 5-generation UK family, linkage analysis identified the locus 9q31.2-q34.2 as a candidate region for AIS; however, the causative gene remained unidentified. Here, using exome sequencing we identified a rare insertion c.1569_1570insTT in the tubulin tyrosine ligase like gene, member 11 (TTLL11) within that locus, as the IS causative gene in this British family. Two other TTLL11 mutations were also identified in two additional AIS cases in the same cohort. Analyses of primary cells of individuals carrying the c.1569_1570insTT (NM_194252) mutation reveal a defect at the primary cilia level, which is less present, smaller and less polyglutamylated compared to control. Further, in a zebrafish, the knock down of ttll11, and the mutated ttll11 confirmed its role in spine development and ciliary function in the fish retina. These findings provide evidence that mutations in TTLL11, a ciliary gene, contribute to the pathogenesis of IS.Hélène MathieuShunmoogum A. PattenJose Antonio Aragon-MartinLouise OcakaMichael SimpsonAnne ChildFlorina MoldovanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hélène Mathieu Shunmoogum A. Patten Jose Antonio Aragon-Martin Louise Ocaka Michael Simpson Anne Child Florina Moldovan Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family
description	Abstract Idiopathic scoliosis (IS) is a complex 3D deformation of the spine with a strong genetic component, most commonly found in adolescent girls. Adolescent idiopathic scoliosis (AIS) affects around 3% of the general population. In a 5-generation UK family, linkage analysis identified the locus 9q31.2-q34.2 as a candidate region for AIS; however, the causative gene remained unidentified. Here, using exome sequencing we identified a rare insertion c.1569_1570insTT in the tubulin tyrosine ligase like gene, member 11 (TTLL11) within that locus, as the IS causative gene in this British family. Two other TTLL11 mutations were also identified in two additional AIS cases in the same cohort. Analyses of primary cells of individuals carrying the c.1569_1570insTT (NM_194252) mutation reveal a defect at the primary cilia level, which is less present, smaller and less polyglutamylated compared to control. Further, in a zebrafish, the knock down of ttll11, and the mutated ttll11 confirmed its role in spine development and ciliary function in the fish retina. These findings provide evidence that mutations in TTLL11, a ciliary gene, contribute to the pathogenesis of IS.
format	article
author	Hélène Mathieu Shunmoogum A. Patten Jose Antonio Aragon-Martin Louise Ocaka Michael Simpson Anne Child Florina Moldovan
author_facet	Hélène Mathieu Shunmoogum A. Patten Jose Antonio Aragon-Martin Louise Ocaka Michael Simpson Anne Child Florina Moldovan
author_sort	Hélène Mathieu
title	Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family
title_short	Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family
title_full	Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family
title_fullStr	Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family
title_full_unstemmed	Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family
title_sort	genetic variant of ttll11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation uk family
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2c82ae51ab604986949fc32ba08186ed
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Genetic variant of TTLL11 gene and subsequent ciliary defects are associated with idiopathic scoliosis in a 5-generation UK family

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