1: Hum Mutat. 1998;11(2):93-108. 

PAX6 mutations reviewed.

Prosser J, van Heyningen V.

MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.

Mutations in PAX6 are responsible for human aniridia and have also been found in
patients with Peter's 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.

Publication Types:
    Review
    Review, Tutorial

PMID: 9482572 [PubMed - indexed for MEDLINE]


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2: Dev Growth Differ. 1997 Feb;39(1):53-67. 

Cranial anomaly of homozygous rSey rat is associated with a defect in the
migration pathway of midbrain crest cells.

Osumi-Yamashita N, Kuratani S, Ninomiya Y, Aoki K, Iseki S, Chareonvit S, Doi H,
Fujiwara M, Watanabe T, Eto K.

Department of Developmental Biology, Graduate School of Dentistry, Tokyo Medical
and Dental University, Japan.

Craniofacial development of vertebrates depends largely on neural crest
contribution and each subdomain of the crest-derived ectomesenchyme follows its
specific genetic control. The rat small eye (rSey) involves a mutation in the
Pax-6 gene and the external feature of rSey homozygous embryos exhibits
craniofacial defects in ocular and frontonasal regions. In order to identify the
mechanism of craniofacial development, we examined the cranial morphology and
migration of cephalic crest cells in rSey embryos. The chondrocranial defects of
homozygous rSey embryos primarily consisted of spheno-orbital and ethmoidal
anomalies. The former defects appeared to be brought about by the lack of the
eye. In the ethmoid region, the nasal septum and the derivative of the medial
nasal prominence were present, while the rest of the nasal capsule, as well as
the nasal and lachrymal bones, were totally absent except for a pair of
cartilaginous rods in place of the nasal capsule. This suggests that the primary
cranial defect is restricted to the lateral nasal prominence derivatives. Dil
labeling revealed the abnormal migration of crest cells specifically from the
anterior midbrain to the lateral nasal prominence in homozygous rSey embryos.
Pax-6 was not expressed in the crest cells but was strongly expressed in the
frontonasal ectoderm. To determine whether or not this migratory defect actually
resides in environmental cues, normal midbrain crest cells from wild-type
embryos were labeled with Dil and were orthotopically injected into host rSey
embryos. Migration of the donor crest cells into the lateral nasal prominence
was abnormal in homozygous host embryos, while they migrated normally in
wild-type or heterozygous embryos. Therefore, the cranial defects in rSey
homozygous embryos are due to inappropriate substrate for crest cell migration
towards the lateral nasal prominence, which consistently explains the cranial
morphology of homozygous rSey embryos.

PMID: 9079035 [PubMed - indexed for MEDLINE]


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