A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family

Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all ca...

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Main Authors: Zeeshan Gauhar, Leon Tejwani, Uzma Abdullah, Sadia Saeed, Shagufta Shafique, Mazhar Badshah, Jungmin Choi, Weilai Dong, Carol Nelson-Williams, Richard P. Lifton, Janghoo Lim, Ghazala K. Raja
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Language:English
Published: MDPI AG 2022-09-01
Series:Cells
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Online Access:https://www.mdpi.com/2073-4409/11/19/3090
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author Zeeshan Gauhar
Leon Tejwani
Uzma Abdullah
Sadia Saeed
Shagufta Shafique
Mazhar Badshah
Jungmin Choi
Weilai Dong
Carol Nelson-Williams
Richard P. Lifton
Janghoo Lim
Ghazala K. Raja
author_facet Zeeshan Gauhar
Leon Tejwani
Uzma Abdullah
Sadia Saeed
Shagufta Shafique
Mazhar Badshah
Jungmin Choi
Weilai Dong
Carol Nelson-Williams
Richard P. Lifton
Janghoo Lim
Ghazala K. Raja
author_sort Zeeshan Gauhar
collection DOAJ
description Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation <i>ERCC8</i>:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in <i>ERCC8</i> as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. <i>ERCC8</i> plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of <i>ERCC8</i> mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.
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spelling doaj.art-8b4eb39ce0dc404498614cfcd9839e1d2023-11-23T20:02:37ZengMDPI AGCells2073-44092022-09-011119309010.3390/cells11193090A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani FamilyZeeshan Gauhar0Leon Tejwani1Uzma Abdullah2Sadia Saeed3Shagufta Shafique4Mazhar Badshah5Jungmin Choi6Weilai Dong7Carol Nelson-Williams8Richard P. Lifton9Janghoo Lim10Ghazala K. Raja11University Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, PakistanInterdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USAUniversity Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, PakistanUniversity Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, PakistanUniversity Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, PakistanDepartment of Neurology, Pakistan Institute of Medical Sciences (PIMS), Islamabad 04485, PakistanDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510, USALaboratory of Human Genetics and Genomics, Rockefeller University, New York, NY 10065, USADepartment of Genetics, Yale School of Medicine, New Haven, CT 06510, USADepartment of Genetics, Yale School of Medicine, New Haven, CT 06510, USAInterdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USAUniversity Institute of Biochemistry and Biotechnology (UIBB), Pir Mehr Ali Shah Arid Agriculture University Rawalpindi (PMAS-AAUR), Rawalpindi 46300, PakistanAutosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation <i>ERCC8</i>:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in <i>ERCC8</i> as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. <i>ERCC8</i> plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of <i>ERCC8</i> mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.https://www.mdpi.com/2073-4409/11/19/3090autosomal-recessive cerebellar ataxiasARCAcerebellumERCC8
spellingShingle Zeeshan Gauhar
Leon Tejwani
Uzma Abdullah
Sadia Saeed
Shagufta Shafique
Mazhar Badshah
Jungmin Choi
Weilai Dong
Carol Nelson-Williams
Richard P. Lifton
Janghoo Lim
Ghazala K. Raja
A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
Cells
autosomal-recessive cerebellar ataxias
ARCA
cerebellum
ERCC8
title A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
title_full A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
title_fullStr A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
title_full_unstemmed A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
title_short A Novel Missense Mutation in <i>ERCC8</i> Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
title_sort novel missense mutation in i ercc8 i co segregates with cerebellar ataxia in a consanguineous pakistani family
topic autosomal-recessive cerebellar ataxias
ARCA
cerebellum
ERCC8
url https://www.mdpi.com/2073-4409/11/19/3090
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