cDNA cloning of a human homologue 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 trinucleotiderepeat expansion-neuropsychiatric symptoms and the phenomenon of geneticanticipation-may be present in forms of dementia, hereditary ataxia,Parkinsonism, bipolar affective disorder, schizophrenia and autism. Toidentify candidate genes for these disorders, we have screened human braincDNA libraries for the presence of gene fragments containing polymorphictrinucleotide repeats. Here we report the cDNA cloning of CAGR1, originallydetected in a retinal cDNA library. The 2743 bp cDNA contains a 1077 bpopen reading frame encoding 359 amino acids. This amino acid sequence ishomologous (56% amino acid identify and 81% amino acid conservation) to theCaenorhabditis elegans cell fate-determining protein mab-21. CAGR1 isexpressed in several human tissues, most prominently in the cerebellum, asa message of approximately 3.0 kb. The gene was mapped to 13q13, justtelomeric to D13S220. A 5'-untranslated CAG trinucleotide repeat is highlypolymorphic, with repeat length ranging from six to 31 triplets and aheterozygosity of 87-88% in 684 chromosomes from several human populations.One allele from an individual with an atypical movement disorder andbipolar affective disorder type II contains 46 triplets, 15 triplets longerthan any other allele detected. Though insufficient data are available tolink the long repeat to this clinical phenotype, an expansion mutation ofthe CAGR1 repeat can be considered a candidate for the etiology ofdisorders with anticipation or developmental abnormalities, andparticularly any such disorders linked to chromosome 13.