title: Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.
abstract: Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations.
authors.affiliation: Division of Human Genetics, National Health Laboratory Service, Johannesburg, South Africa.|Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Amanda
authors.initials: A
authors.lastname: Krause
authors.affiliation: Division of Human Genetics, National Health Laboratory Service, Johannesburg, South Africa.
authors.forename: Claire
authors.initials: C
authors.lastname: Mitchell
authors.affiliation: Division of Human Genetics, National Health Laboratory Service, Johannesburg, South Africa.|Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Fahmida
authors.initials: F
authors.lastname: Essop
authors.affiliation: Department of Neurology, University of the Witwatersrand, Johannesburg, South Africa.|Donald Gordon Medical Centre, Johannesburg, South Africa.
authors.forename: Susan
authors.initials: S
authors.lastname: Tager
authors.affiliation: Department of Neurology, University of the Witwatersrand, Johannesburg, South Africa.|Department Clinical Neurology, University of Adelaide and the Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Temlett
authors.affiliation: Sorbonne Universités, UPMC Univ Paris, Institut du Cerveau et de la Moelle épinière, Paris, France.|Ecole Pratique des Hautes Etudes, Paris, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: Johns Hopkins University School of Medicine, Departments of Psychiatry, Neurology, Neuroscience, and Pharmacology and Molecular Sciences and Program in Cellular and Molecular Medicine, Baltimore, Maryland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ross
authors.affiliation: Johns Hopkins University School of Medicine, Departments of Psychiatry and Program in Cellular and Molecular Medicine, Baltimore, Maryland.
authors.forename: Dobrila
authors.initials: D
authors.lastname: Rudnicki
authors.affiliation: Johns Hopkins University School of Medicine, Departments of Psychiatry and Neurology and Program in Cellular and Molecular Medicine, Baltimore, Maryland.
authors.forename: Russell
authors.initials: R
authors.lastname: Margolis
mesh_terms: D000328:Adult; D044383:Black People / Q000235:genetics; D002819:Chorea / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D003072:Cognition Disorders / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D003704:Dementia / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D020271:Heredodegenerative Disorders, Nervous System / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006816:Huntington Disease / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013019:South Africa; D018911:Trinucleotide Repeats; D044465:White People / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C412507:junctophilin
keywords: African; Huntington; Huntington disease-like; junctophilin; trinucleotide repeat expansion