Jane Prosser

PAX6 mutations reviewed

Mutations inPAX6 are responsible for human aniridia and have also been found in patients with Peters anomaly, with congenital cataracts, with autosomal dominant keratitis, and with isolated foveal hypoplasia. No locus other than chromosome 11p13 has been implicated in aniridia, and PAX6 is clearly the major, if not only, gene responsible. Twenty‐eight percent of identified PAX6 mutations are C–T changes at CpG dinucleotides, 20% are splicing errors, and more than 30% are deletion or insertion events. There is a noticeably elevated level of mutation in the paired domain compared with the rest of the gene. Increased mutation in the homeodomain is accounted for by the hypermutable CpG dinucleotide in codon 240. Very nearly all mutations appear to cause loss of function of the mutant allele, and more than 80% of exonic substitutions result in nonsense codons. In a gene with such extraordinarily high sequence conservation throughout evolution, there are presumed undiscovered missense mutations, these are hypothesized to exist in as‐yet unidentified phenotypes. Hum Mutat 11:93–108, 1998.

The human PAX6 mutation database

The Human PAX6 Mutation Database contains details of 94 mutations of the PAX6 gene. A Microsoft Access program is used by the Curator to store, update and search the database entries. Mutations can be entered directly by the Curator, or imported from submissions made via the World Wide Web. The PAX6 Mutation Database web page at URL http://www.hgu.mrc.ac.uk/Softdata/PAX6/ provides information about PAX6, as well as a fill-in form through which new mutations can be submitted to the Curator. A search facility allows remote users to query the database. A plain text format file of the data can be downloaded via the World Wide Web. The Curation program contains prior knowledge of the genetic code and of the PAX6 gene including cDNA sequence, location of intron/exon boundaries, and protein domains, so that the minimum of information need be provided by the submitter or Curator.

Detecting single-base mutations

The ability to detect single-base changes is of fundamental importance in molecular genetics. This is particularly true in human genetics, where interest in linking mutations of identified genes to particular disease phenotypes is most intense, and where a demand exists for clinical diagnosis of defined mutations. In the following article, techniques are described for screening unknown mutations, as well as diagnosing those that have been identified previously. The underlying methods are explained briefly and guidelines are offered for choosing one technique in preference to another.