PMID- 10441571
OWN - NLM
STAT- MEDLINE
DCOM- 19991004
LR  - 20200824
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 65
IP  - 3
DP  - 1999 Sep
TI  - Missense mutation in the alternative splice region of the PAX6 gene in eye
      anomalies.
PG  - 656-63
AB  - The PAX6 gene is involved in ocular morphogenesis, and PAX6 mutations have been
      detected in various types of ocular anomalies, including aniridia, Peters
      anomaly, corneal dystrophy, congenital cataract, and foveal hypoplasia. The gene 
      encodes a transcriptional regulator that recognizes target genes through its
      paired-type DNA-binding domain. The paired domain is composed of two distinct
      DNA-binding subdomains, the N-terminal subdomain (NTS) and the C-terminal
      subdomain (CTS), which bind respective consensus DNA sequences. The human PAX6
      gene produces two alternative splice isoforms that have the distinct structure of
      the paired domain. The insertion, into the NTS, of 14 additional amino acids
      encoded by exon 5a abolishes the DNA-binding activity of the NTS and unmasks the 
      DNA-binding ability of the CTS. Thus, exon 5a appears to function as a molecular 
      switch that specifies target genes. We ascertained a novel missense mutation in
      four pedigrees with Peters anomaly, congenital cataract, Axenfeldt anomaly,
      and/or foveal hypoplasia, which, to our knowledge, is the first mutation
      identified in the splice-variant region. A T-->A transition at the 20th
      nucleotide position of exon 5a results in a Val-->Asp (GTC-->GAC) substitution at
      the 7th codon of the alternative splice region. Functional analyses demonstrated 
      that the V54D mutation slightly increased NTS binding and decreased CTS
      transactivation activity to almost half.
FAU - Azuma, N
AU  - Azuma N
AD  - Department of Ophthalmology, National Children's Hospital, Tokyo 154-8509, Japan.
      nazuma@nch.go.jp
FAU - Yamaguchi, Y
AU  - Yamaguchi Y
FAU - Handa, H
AU  - Handa H
FAU - Hayakawa, M
AU  - Hayakawa M
FAU - Kanai, A
AU  - Kanai A
FAU - Yamada, M
AU  - Yamada M
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Eye Proteins)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (PAX6 Transcription Factor)
RN  - 0 (PAX6 protein, human)
RN  - 0 (Paired Box Transcription Factors)
RN  - 0 (Protein Isoforms)
RN  - 0 (Repressor Proteins)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Abnormalities, Multiple/genetics/physiopathology
MH  - Adolescent
MH  - Adult
MH  - Alternative Splicing/*genetics
MH  - Amino Acid Substitution
MH  - Base Sequence
MH  - Child, Preschool
MH  - DNA/genetics/metabolism
MH  - DNA-Binding Proteins/chemistry/*genetics/*metabolism
MH  - Exons/genetics
MH  - Eye Abnormalities/*genetics/physiopathology
MH  - Eye Proteins
MH  - Female
MH  - *Homeodomain Proteins
MH  - Humans
MH  - Infant
MH  - Japan
MH  - Male
MH  - Mutation, Missense/*genetics
MH  - PAX6 Transcription Factor
MH  - Paired Box Transcription Factors
MH  - Phenotype
MH  - Polymorphism, Single-Stranded Conformational
MH  - Protein Binding
MH  - Protein Isoforms/chemistry/genetics/metabolism
MH  - Repressor Proteins
MH  - Transcriptional Activation
PMC - PMC1377971
EDAT- 1999/08/12 10:00
MHDA- 2000/03/21 09:00
CRDT- 1999/08/12 10:00
PHST- 1999/08/12 10:00 [pubmed]
PHST- 2000/03/21 09:00 [medline]
PHST- 1999/08/12 10:00 [entrez]
AID - S0002-9297(07)62316-7 [pii]
AID - 10.1086/302529 [doi]
PST - ppublish
SO  - Am J Hum Genet. 1999 Sep;65(3):656-63. doi: 10.1086/302529.