Mutational mechanisms

The complexity of both the patterns of inheritance and phenotypes of psychiatric disorders suggests that the underlying genetic abnormalities are equally complex. In fact there is probably nothing unique about the molecular defects, although it has to be admitted that we know next to nothing about the molecular basis of common psychiatric conditions. Where mutations have been described in single genes that give rise to behavioural disorders, they are typical of other human genetic disorders; changes in a single base pair (e.g. from C to T) of the coding sequence of the gene may alter the function of the protein ( mis-sense mutations), result in premature termination of the protein product (non-sense mutations), or create or destroy a splice site. In addition, deletions (of a single base pair or many megabases of DNA) and insertions (again of any size) disrupt transcription and translation of a gene. Deletions or insertions that do not affect a multiple of three bases alter the way that the message is translated and are known as frame-shift mutations. None of these mechanisms is special to psychiatric genetics and by themselves tells us nothing about how the mutation produces the disorder.

One mutational mechanism that does deserve special comment is expansion of trinucleotide repeats.(25) Its importance in psychiatry is that it occurs in neurological disorders, some with behavioural phenotypes, and in two mental retardation syndromes (Table 1). No one knows why trinucleotide repeat expansions tend to be found in disorders of the central nervous system, and the unusual mutational mechanism has not so far explained the pathogenesis of any of the disorders in which it occurs. The mechanism was first discovered in 1991 as the cause of fragile X syndrome, a common form of inherited X-linked mental retardation. (26>

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Table 1 Triplet repeat diseases

Table 1 Triplet repeat diseases

The most common repeat types are AGC and CGG (TabJe.1) which can expand dramatically from a small array in unaffected individuals to many hundreds of copies. At each locus there is a normal range of copy numbers above which the repeat array becomes unstable—the larger the number of copies, the more unstable is the allele. Furthermore, larger alleles result in more severe disease with earlier onset. The consequence is that the age of onset of a disorder may become progressively earlier with each new generation of affected individuals in a pedigree, a phenomenon called anticipation. The association between trinucleotide repeat expansions and central nervous system disorders, together with claims that anticipation occurs in manic-depressive psychosis and, less credibly, in schizophrenia, prompted a search for expanded trinucleotide repeats in the psychoses. The results, although preliminary, suggest that schizophrenics may have an excess of expanded trinucleotide repeats compared with controls.(27,28 and 29> However, it should again be stressed that molecular mechanisms have not yet told us anything about pathogenesis.

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