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. 2015 Oct;168(7):573-85.
doi: 10.1002/ajmg.b.32332. Epub 2015 Jun 16.

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

Amanda Krause  1   2 , Claire Mitchell  1 , Fahmida Essop  1   2 , Susan Tager  3   4 , James Temlett  3   5 , Giovanni Stevanin  6   7 , Christopher Ross  8 , Dobrila Rudnicki  9 , Russell Margolis  10
Affiliations

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

Amanda Krause et al. Am J Med Genet B Neuropsychiatr Genet. 2015 Oct.

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.

Keywords: African; Huntington; Huntington disease-like; junctophilin; trinucleotide repeat expansion.

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Figures

Figure 1
Figure 1
Triplet repeat distributions in patients with HD and HDL2. (Three HTT alleles with repeat size greater than 58 not shown).
Figure 2
Figure 2
Age of diagnosis vs number of repeats in patients with HDL2
Figure 3
Figure 3
JPH3 CTG repeat distributions in 134 white and 176 black unaffected individuals
Figure 4
Figure 4
Summary of the likely disease-associated haplotypes for all HDL2 families studied. The relative positions of the SNP and microsatellite markers used for haplotype analysis are also shown. aUnequivocal haplotype determined from family study bAncestry from Europe, American Indian, Africa NR, no result
Figure 5
Figure 5
Microsatellite allele distribution for markers (A) D16S3074, (B) D16S3048, and (C) D16S413 around the JPH3 locus
See this image and copyright information in PMC

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