ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

University of Washington Center for Mendelian Genomics; Laura J Niedernhofer

doi:10.1002/humu.23367

ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

University of Washington Center for Mendelian Genomics, Laura J Niedernhofer

Research output: Contribution to journal › Article › peer-review

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Abstract

Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

Original language	English (US)
Pages (from-to)	255-265
Number of pages	11
Journal	Human mutation
Volume	39
Issue number	2
DOIs	https://doi.org/10.1002/humu.23367
State	Published - Feb 2018

Bibliographical note

Funding Information:
The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities.

Funding Information:
Contract Grant Sponsors: National Institutes of Health grants (R24AG42328, R01CA210916, P01AG043376); National Institutes of Health /National Human Genome Research Institute; National Institutes of Health /National Heart, Lung, and Blood Institute (U54HG006493); WeNMR (261572).

Funding Information:
The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. The authors declare no conflict of interest.

Publisher Copyright:
© 2017 Wiley Periodicals, Inc.

Keywords

Atypical Werner syndrome
Cockayne syndrome
ERCC4
Mendelian disease
molecular genetics
segmental progeroid syndromes
xeroderma pigmentosum group F

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/humu.23367

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762268

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@article{25a1509937534db08321764fdf1ffb91,

title = "ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes",

abstract = "Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.",

keywords = "Atypical Werner syndrome, Cockayne syndrome, ERCC4, Mendelian disease, molecular genetics, segmental progeroid syndromes, xeroderma pigmentosum group F",

author = "{University of Washington Center for Mendelian Genomics} and Takayasu Mori and Yousefzadeh, {Matthew J.} and Maryam Faridounnia and Chong, {Jessica X.} and Hisama, {Fuki M.} and Louanne Hudgins and Gabriela Mercado and Wade, {Erin A.} and Barghouthy, {Amira S.} and Lin Lee and Martin, {George M.} and Nickerson, {Deborah A.} and Bamshad, {Michael J.} and Niedernhofer, {Laura J}",

note = "Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. Funding Information: Contract Grant Sponsors: National Institutes of Health grants (R24AG42328, R01CA210916, P01AG043376); National Institutes of Health /National Human Genome Research Institute; National Institutes of Health /National Heart, Lung, and Blood Institute (U54HG006493); WeNMR (261572). Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. The authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",

year = "2018",

month = feb,

doi = "10.1002/humu.23367",

language = "English (US)",

volume = "39",

pages = "255--265",

journal = "Human mutation",

issn = "1059-7794",

publisher = "John Wiley and Sons Inc.",

number = "2",

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TY - JOUR

T1 - ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

AU - University of Washington Center for Mendelian Genomics

AU - Mori, Takayasu

AU - Yousefzadeh, Matthew J.

AU - Faridounnia, Maryam

AU - Chong, Jessica X.

AU - Hisama, Fuki M.

AU - Hudgins, Louanne

AU - Mercado, Gabriela

AU - Wade, Erin A.

AU - Barghouthy, Amira S.

AU - Lee, Lin

AU - Martin, George M.

AU - Nickerson, Deborah A.

AU - Bamshad, Michael J.

AU - Niedernhofer, Laura J

N1 - Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. Funding Information: Contract Grant Sponsors: National Institutes of Health grants (R24AG42328, R01CA210916, P01AG043376); National Institutes of Health /National Human Genome Research Institute; National Institutes of Health /National Heart, Lung, and Blood Institute (U54HG006493); WeNMR (261572). Funding Information: The WeNMR project (European FP7 e-Infrastructure grant, contract no. 261572, www.wenmr.eu), supported by the European Grid Initiative (EGI) through the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan, the Latin America GRID infrastructure via the Gisela project, and the US Open Science Grid (OSG) are acknowledged for the use of web portals, computing, and storage facilities. The authors declare no conflict of interest. Publisher Copyright: © 2017 Wiley Periodicals, Inc.

PY - 2018/2

Y1 - 2018/2

N2 - Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

AB - Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

KW - Atypical Werner syndrome

KW - Cockayne syndrome

KW - ERCC4

KW - Mendelian disease

KW - molecular genetics

KW - segmental progeroid syndromes

KW - xeroderma pigmentosum group F

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U2 - 10.1002/humu.23367

DO - 10.1002/humu.23367

M3 - Article

C2 - 29105242

AN - SCOPUS:85034262701

SN - 1059-7794

VL - 39

SP - 255

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JO - Human mutation

JF - Human mutation

IS - 2

ER -

ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes

Abstract

Bibliographical note

Keywords

UN SDGs

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