Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia.
We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8). SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family. SCA8 expansions have also been found in control chromosomes, indicating that separate genetic or environmental factors increase disease penetrance among SCA8-expansion-carrying patients with ataxia. We describe the molecular genetic features and disease penetrance of 37 different families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. Haplotype analysis using 17 STR markers spanning an approximately 1-Mb region was performed on the families with ataxia, on a group of expansion carriers in the general population, and on psychiatric patients, to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). Our finding that SCA8 expansions on three independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supports the direct role of the CTG expansion in disease pathogenesis.
Ikeda
Yoshio
Y
Institute of Human Genetics and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, 55455, USA.
Dalton
Joline C
JC
Moseley
Melinda L
ML
Gardner
Kathy L
KL
Bird
Thomas D
TD
Ashizawa
Tetsuo
T
Seltzer
William K
WK
Pandolfo
Massimo
M
Milunsky
Aubrey
A
Potter
Nicholas T
NT
Shoji
Mikio
M
Vincent
John B
JB
Day
John W
JW
Ranum
Laura P W
LP
D016022:Case-Control Studies; D020090:Chromosome Segregation; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008967:Molecular Biology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D011618:Psychotic Disorders / Q000235:genetics* / Q000473:pathology; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion
C415906:ATXN8OS gene product, human; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated