Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability

Francesca Mattioli, Bertrand Isidor, Omar Abdul-Rahman, Andrew Gunter, Lijia Huang, Raman Kumar, Chandree Beaulieu, Jozef Gecz, Micheil Innes, Jean Louis Mandel, Amelie Piton

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

THOC6 encodes a subunit of the THO complex that is part of a highly-conserved TREX complex, known to have roles in mRNA processing and export. Few homozygous or compound heterozygote variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability (ID) (Beaulieu-Boycott-Innes syndrome, BBIS MIM# 613680). Here we report two additional individuals affected with BBIS originating from the north of Europe and sharing an haplotype composed by threevery rare missense changes in the THOC6gene: p.(Trp100Arg; Val234Leu; Gly275Asp). The first individual is a boy who is homozygous for the three-variant haplotype, due to a maternal uniparental disomy event. The second is a girl, who is compound heterozygote for this haplotype and a previously reported p.(Gly190Glu) missense variant. We analyzed the impact of these different amino acid changes on THOC6 protein expression,cellular localization, and interaction with the other THO complex subunits. We show that the different THOC6 variants alter the physiological nuclear localization of the protein and its interaction with at least two THO subunits, THOC1 and THOC5. Two amino acid changes from the three-variant-haplotype have alone specific effects and might contribute to the pathogenicity of the haplotype. Overall, we expanded the cohort of currently known BBIS affected individuals by reporting two individuals carrying the same recurrent European haplotype composed of three amino acid changes, affecting THOC6 localization and interaction with THO protein partners.

LanguageEnglish
Pages952-960
Number of pages9
JournalHuman molecular genetics
Volume28
Issue number6
Early online date21 Nov 2018
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Journal Article

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mattioli, Francesca ; Isidor, Bertrand ; Abdul-Rahman, Omar ; Gunter, Andrew ; Huang, Lijia ; Kumar, Raman ; Beaulieu, Chandree ; Gecz, Jozef ; Innes, Micheil ; Mandel, Jean Louis ; Piton, Amelie. / Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. In: Human molecular genetics. 2019 ; Vol. 28, No. 6. pp. 952-960.
@article{02a51dd2cef14f7a8666d80e498ca32e,
title = "Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability",
abstract = "THOC6 encodes a subunit of the THO complex that is part of a highly-conserved TREX complex, known to have roles in mRNA processing and export. Few homozygous or compound heterozygote variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability (ID) (Beaulieu-Boycott-Innes syndrome, BBIS MIM# 613680). Here we report two additional individuals affected with BBIS originating from the north of Europe and sharing an haplotype composed by threevery rare missense changes in the THOC6gene: p.(Trp100Arg; Val234Leu; Gly275Asp). The first individual is a boy who is homozygous for the three-variant haplotype, due to a maternal uniparental disomy event. The second is a girl, who is compound heterozygote for this haplotype and a previously reported p.(Gly190Glu) missense variant. We analyzed the impact of these different amino acid changes on THOC6 protein expression,cellular localization, and interaction with the other THO complex subunits. We show that the different THOC6 variants alter the physiological nuclear localization of the protein and its interaction with at least two THO subunits, THOC1 and THOC5. Two amino acid changes from the three-variant-haplotype have alone specific effects and might contribute to the pathogenicity of the haplotype. Overall, we expanded the cohort of currently known BBIS affected individuals by reporting two individuals carrying the same recurrent European haplotype composed of three amino acid changes, affecting THOC6 localization and interaction with THO protein partners.",
keywords = "Journal Article",
author = "Francesca Mattioli and Bertrand Isidor and Omar Abdul-Rahman and Andrew Gunter and Lijia Huang and Raman Kumar and Chandree Beaulieu and Jozef Gecz and Micheil Innes and Mandel, {Jean Louis} and Amelie Piton",
year = "2019",
month = "1",
day = "1",
doi = "10.1093/hmg/ddy391",
language = "English",
volume = "28",
pages = "952--960",
journal = "Human molecular genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "6",

}

Mattioli, F, Isidor, B, Abdul-Rahman, O, Gunter, A, Huang, L, Kumar, R, Beaulieu, C, Gecz, J, Innes, M, Mandel, JL & Piton, A 2019, 'Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability', Human molecular genetics, vol. 28, no. 6, pp. 952-960. https://doi.org/10.1093/hmg/ddy391

Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. / Mattioli, Francesca; Isidor, Bertrand; Abdul-Rahman, Omar; Gunter, Andrew; Huang, Lijia; Kumar, Raman; Beaulieu, Chandree; Gecz, Jozef; Innes, Micheil; Mandel, Jean Louis; Piton, Amelie.

In: Human molecular genetics, Vol. 28, No. 6, 01.01.2019, p. 952-960.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability

AU - Mattioli, Francesca

AU - Isidor, Bertrand

AU - Abdul-Rahman, Omar

AU - Gunter, Andrew

AU - Huang, Lijia

AU - Kumar, Raman

AU - Beaulieu, Chandree

AU - Gecz, Jozef

AU - Innes, Micheil

AU - Mandel, Jean Louis

AU - Piton, Amelie

PY - 2019/1/1

Y1 - 2019/1/1

N2 - THOC6 encodes a subunit of the THO complex that is part of a highly-conserved TREX complex, known to have roles in mRNA processing and export. Few homozygous or compound heterozygote variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability (ID) (Beaulieu-Boycott-Innes syndrome, BBIS MIM# 613680). Here we report two additional individuals affected with BBIS originating from the north of Europe and sharing an haplotype composed by threevery rare missense changes in the THOC6gene: p.(Trp100Arg; Val234Leu; Gly275Asp). The first individual is a boy who is homozygous for the three-variant haplotype, due to a maternal uniparental disomy event. The second is a girl, who is compound heterozygote for this haplotype and a previously reported p.(Gly190Glu) missense variant. We analyzed the impact of these different amino acid changes on THOC6 protein expression,cellular localization, and interaction with the other THO complex subunits. We show that the different THOC6 variants alter the physiological nuclear localization of the protein and its interaction with at least two THO subunits, THOC1 and THOC5. Two amino acid changes from the three-variant-haplotype have alone specific effects and might contribute to the pathogenicity of the haplotype. Overall, we expanded the cohort of currently known BBIS affected individuals by reporting two individuals carrying the same recurrent European haplotype composed of three amino acid changes, affecting THOC6 localization and interaction with THO protein partners.

AB - THOC6 encodes a subunit of the THO complex that is part of a highly-conserved TREX complex, known to have roles in mRNA processing and export. Few homozygous or compound heterozygote variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability (ID) (Beaulieu-Boycott-Innes syndrome, BBIS MIM# 613680). Here we report two additional individuals affected with BBIS originating from the north of Europe and sharing an haplotype composed by threevery rare missense changes in the THOC6gene: p.(Trp100Arg; Val234Leu; Gly275Asp). The first individual is a boy who is homozygous for the three-variant haplotype, due to a maternal uniparental disomy event. The second is a girl, who is compound heterozygote for this haplotype and a previously reported p.(Gly190Glu) missense variant. We analyzed the impact of these different amino acid changes on THOC6 protein expression,cellular localization, and interaction with the other THO complex subunits. We show that the different THOC6 variants alter the physiological nuclear localization of the protein and its interaction with at least two THO subunits, THOC1 and THOC5. Two amino acid changes from the three-variant-haplotype have alone specific effects and might contribute to the pathogenicity of the haplotype. Overall, we expanded the cohort of currently known BBIS affected individuals by reporting two individuals carrying the same recurrent European haplotype composed of three amino acid changes, affecting THOC6 localization and interaction with THO protein partners.

KW - Journal Article

UR - http://www.scopus.com/inward/record.url?scp=85066755318&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddy391

DO - 10.1093/hmg/ddy391

M3 - Article

VL - 28

SP - 952

EP - 960

JO - Human molecular genetics

T2 - Human molecular genetics

JF - Human molecular genetics

SN - 0964-6906

IS - 6

ER -