CDNA CLONING OF A HUMAN HOMOLOG OF THE CAENORHABDITIS-ELEGANS CELL FATE-DETERMINING GENE MAB-21 - EXPRESSION, CHROMOSOMAL LOCALIZATION AND ANALYSIS OF A HIGHLY POLYMORPHIC (CAG)(N) TRINUCLEOTIDE REPEAT

The two most consistent features of the diseases caused by trinucleoti de repeat expansion-neuropsychiatric symptoms and the phenomenon of ge netic anticipation-may be present in forms of dementia, hereditary ata xia, Parkinsonism, bipolar affective disorder, schizophrenia and autis m. To identify candidate genes for these disorders, we have screened h uman brain cDNA libraries for the presence of gene fragments containin g polymorphic trinucleotide repeats. Here we report the cDNA cloning o f CAGR1, originally detected in a retinal cDNA library. The 2743 bp cD NA contains a 1077 bp open reading frame encoding 359 amino acids. Thi s amino acid sequence is homologous (56% amino acid identity and 81% a mino acid conservation) to the Caenorhabditis elegans cell fate-determ ining protein mab-21. CAGR1 is expressed in several human tissues, mos t prominently in the cerebellum, as a message of similar to 3.0 kb. Th e gene was mapped to 13q13, just telomeric to D13S220. A 5'-untranslat ed CAG trinucleotide repeat is highly polymorphic, with repeat length ranging from six to 31 triplets and a heterozygosity of 87-88% in 684 chromosomes from several human populations. One allele from an individ ual with an atypical movement disorder and bipolar affective disorder type II contains 46 triplets, 15 triplets longer than any other allele detected. Though insufficient data are? available to link the long re peat to this clinical phenotype, an expansion mutation of the CAGR1 re peat can be considered a candidate for the etiology of disorders with anticipation or developmental abnormalities, and particularly any such disorders linked to chromosome 13.