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Huntington's disease: Genetic heterogeneity in black African patients

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      Abstract

      OBJECTIVE: Huntington's disease (HD) has been reported to occur rarely in black patients. A new genetic variant-Huntington's disease-like 2 (HDL2) - occurring more frequently in blacks, has recently been described. The absence of an expanded trinucleotide repeat at the chromosome 4 HD locus was previously regarded as a way of excluding classic HD. The objective of this paper is to describe a number of black patients with genetically proven HD and to review its occurrence in Africa. METHODS: Eleven black families (12 subjects), with genetically proven HD, are described: 9 from the Dr George Mukhari Hospital, and 2 from private practice in Tshwane. RESULTS: Chorea was present in all 12 patients and cognitive decline in 9. Nine had an age of onset between 30 and 50 years. Six families exhibited expansion of the trinucleotide repeat at the chromosome 4, IT 15 gene (HD), and 5 a junctophilin (JPH3) trinucleotide expansion at chromosome 16 (HDL2). The HDL2 subtype showed a tendency towards a later age of onset. CONCLUSIONS: The clinical presentation of the two genotypes (i.e. HD and HDL2) appears to be similar. The actual rate of occurrence of HD in blacks may require re-assessment. Considering the number of Huntington's chorea patients occurring in our area (Garankuwa), the possibility of clustering of the condition arises.

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      Most cited references 38

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      Junctophilins: a novel family of junctional membrane complex proteins.

       M Iino,  H Takeshima,  M Nishi (2000)
      Junctional complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/ SR) are a common feature of all excitable cell types and mediate cross-talk between cell surface and intracellular ion channels. We have identified the junctophilins (JPs), a novel conserved family of proteins that are components of the junctional complexes. JPs are composed of a carboxy-terminal hydrophobic segment spanning the ER/SR membrane and a remaining cytoplasmic domain that shows specific affinity for the PM. In mouse, there are at least three JP subtypes: JP-1, -2, and -3. JP-2 is abundantly expressed in the heart, and mutant mice lacking JP-2 exhibited embryonic lethality. Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal Ca2+ transients. Our results suggest that JPs are important components of junctional membrane complexes.
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        A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats.

        Huntington's disease is associated with an expanded sequence of CAG repeats in a gene on chromosome 4p16.3. However, neither the sensitivity of expanded CAG repeats in affected persons of different ethnic origins nor the specificity of such repeats for Huntington's disease as compared with other neuropsychiatric disorders has been determined. We studied 1007 patients with diagnosed Huntington's disease from 565 families and 43 national and ethnic groups. In addition, the length of the CAG repeat was determined in 113 control subjects with a family history of Alzheimer's disease (44 patients), schizophrenia (39), major depression (16), senile chorea (5), benign hereditary chorea (5), neuroacanthocytosis (2), and dentatorubropallidoluysian atrophy (2). The number of CAG repeats was also assessed in 1595 control chromosomes, with the size of adjacent polymorphic CCG trinucleotide repeats taken into account. Of 1007 patients with signs and symptoms compatible with a diagnosis of Huntington's disease, 995 had an expanded CAG repeat that included from 36 to 121 repeats (median, 44) (sensitivity, 98.8 percent; 95 percent confidence interval, 97.7 to 99.4 percent). There were no significant differences among national and ethnic groups in the number of repeats. No CAG expansion was found in the 110 control subjects with other neuropsychiatric disorders (specificity, 100 percent; 95 percent confidence interval, 95.2 to 100 percent). In 1581 of the 1595 control chromosomes (99.1 percent), the number of CAG repeats ranged from 10 to 29 (median, 18). In 12 control chromosomes (0.75 percent), intermediate-sized CAG sequences with 30 to 35 repeats were found, and 2 normal chromosomes unexpectedly had expanded CAG sequences, of 39 and 37 repeats. CAG trinucleotide expansion is the molecular basis of Huntington's disease worldwide and is a highly sensitive and specific marker for inheritance of the disease mutation.
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          A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2.

          We recently described a disorder termed Huntington disease-like 2 (HDL2) that completely segregates with an unidentified CAG/CTG expansion in a large pedigree (W). We now report the cloning of this expansion and its localization to a variably spliced exon of JPH3 (encoding junctophilin-3), a gene involved in the formation of junctional membrane structures.
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            Author and article information

            Affiliations
            [1 ] University of Limpopo
            [2 ] University of the Witwatersrand
            Contributors
            Role: ND
            Role: ND
            Role: ND
            Role: ND
            Role: ND
            Role: ND
            Role: ND
            Journal
            samj
            SAMJ: South African Medical Journal
            SAMJ, S. Afr. med. j.
            Health and Medical Publishing Group (Cape Town )
            2078-5135
            March 2008
            : 98
            : 3
            : 200-203
            S0256-95742008000300020

            http://creativecommons.org/licenses/by/4.0/

            Product
            Product Information: SciELO South Africa
            Categories
            Health Care Sciences & Services
            Health Policy & Services
            Medical Ethics
            Medicine, General & Internal
            Medicine, Legal
            Medicine, Research & Experimental

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