Trinucleotide repeats and neuropsychiatric phenotypes

• Main Author: Yuan, Qiu-Ping
• Format: Doctoral or Postdoctoral Thesis
• Language: unknown
• Published: Institutionen för molekylär medicin / Department of Molecular Medicine 2001
• Subjects: Trinucleotide; repeat expansion; psychiatric disorder; gene; spastic paraplegia; Northern Sweden
• Online Access: http://hdl.handle.net/10616/42725

Genetic studies of affective disorders have yielded several chromosomal regions suggestive for linkage. Linkage analysis was performed in five families with unipolar affective disorder, collected from northern Sweden. Four candidate regions on chromosomes 16, 18, 21 and 4p were excluded. Anticipation, increased disease severity and younger age-of-onset in successive family generations correlating with a longer repeat expansion, is a hallmark in disorders caused by trinucleotide repeat expansions (TREs). Mental impairment and psychiatric symptoms are seen in some of these disorders. This study aimed at investigating if TREs may be susceptibility factors for neuropsychiatric disorders displaying anticipation. Fourteen Swedish families with affective disorders displaying anticipation were screened for CAG/CTG expansions as a possible explanation for the observed anticipation using the repeat expansion detection (RED) method. A significant difference in CAG/CTG repeat expansion distribution between affected offspring and healthy family members was seen. Two loci, ERDA1 on chromosome 17 and CTG18.1 on chromosome 18 were analyzed by PCR in the families. Eighty-nine percent of the RED expansions correlated in size with large alleles at these two loci. CTG18.1 expansions were more frequently seen in patients as compared to healthy individuals (odds ratio 2.6-2.8), and their size correlated inversely with age-of-onset. The allele distribution at ERDA1 was not significantly different between patients and healthy individuals. Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder associated with a CTG repeat expansion. The SCA8 repeat was analyzed using PCR in four sets of family and case-control materials of different origin. The frequency of individuals with expanded SCA8 repeats (>40 repeats) was higher in all the four patient groups as compared to healthy individuals. Expanded alleles within the SCA8 pathogenic size range (107-127 CTG repeats) were detected in 5 affected individuals and two healthy ...