A survey of trinucleotide/tandem repeat-containing transcripts (TNRTs) isolated from human spinal cord to identify genes containing unstable DNA regions as candidates for disorders of motor function

Expansion of unstable DNA regions containing trinucleotide/tandem repeats ( TNRs) represents a common genetic mutation in hereditary forms of neurologi cal disorders. The spectrum of neurological diseases linked to TNR expansio ns has recently broadened to include conditions with both dominant and rece ssive inheritance and those with or without clinical anticipation. In view of the frequent involvement of the spinal cord in neurodegenerative disorde rs, we have analysed this key tissue to identify pathological TNRs. We have used two approaches to isolate a wide range of trinucleotide/tandem repeat -containing transcripts (TNRTs) from human spinal cord, firstly a polymeras e chain reaction (PCR)-based method and secondly by screening a spinal cord cDNA library immobilised on a membrane. Overall, 97 TNRTs belonging to a n umber of key protein families, the most highly represented being transcript ion factors, intracellular signalling molecules and cytoskeletal proteins, have been isolated most of which have not previously been considered as pot ential disease-causing genes. The commonest repeat motifs found in our stud y were CAG (37%) and CCG (24%). Known genes involved in DNA repeat expansio n-related neurological disorders (e.g., AAD10, Ataxin-3, Huntingtin) were d etected which validated our methods. We have characterised homogeneous TNRs among the detected gene candidates in a search for potential pathological repeat expansions. The potential role of the gene candidates identified is discussed in terms of their contribution to neurodegenerative processes. (C ) 2001 Elsevier Science Inc.