PMID- 18222992
OWN - NLM
STAT- MEDLINE
DCOM- 20080423
LR  - 20211027
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Linking)
VI  - 131
IP  - Pt 2
DP  - 2008 Feb
TI  - A missense mutation in the murine Opa3 gene models human Costeff syndrome.
PG  - 368-80
LID - 10.1093/brain/awm333 [doi]
AB  - Opa3 mRNA is expressed in all tissues examined to date, but currently the 
      function of the OPA3 protein is unknown. Intriguingly, various mutations in the 
      OPA3 gene lead to two similar diseases in humans: autosomal dominant inherited 
      optic atrophy and cataract (ADOAC) and a metabolic condition; type 
      3-methylglutaconic aciduria (MGA). Early onset bilateral optic atrophy is a 
      common characteristic of both disorders; retinal ganglion cells are lost and 
      visual acuity is impaired from an early age. In order to investigate the function 
      of the OPA3 protein, we have generated a novel ENU-induced mutant mouse carrying 
      a missense mutation in the OPA3 gene. The heterozygous mutation in exon 2, causes 
      an amino acid change p.L122P (c.365T>C), which is predicted to alter tertiary 
      protein structure. In the heterozygous state, the mice appear uncompromised 
      however; in the homozygous state mice display some of the features of MGA. Visual 
      function is severely reduced, consistent with significant loss of retinal 
      ganglion cells and degeneration of axons in the optic nerve. In the homozygous 
      optic nerve, there was evidence of increased mitochondrial activity, as 
      demonstrated by the increased presence of mitochondrial marker Cytochrome C 
      Oxidase (COX) histochemistry. Mice homozygous for the opa3(L122P) mutation also 
      display a severe multi-systemic disease characterized by reduced lifespan 
      (majority dying before 4 months), decreased weight, dilated cardiomyopathy, 
      extrapyramidal dysfunction and gross neuro-muscular defects. All of these defects 
      are synonymous with the phenotypic characteristics of Type III MGA found in 
      humans. This model will be of major importance for future studies of the specific 
      function of the OPA3 gene.
FAU - Davies, Vanessa J
AU  - Davies VJ
AD  - School of Optometry and Vision Sciences, Cardiff University, Maindy Road, 
      Cathays, Cardiff CF24 4LU, UK.
FAU - Powell, Kate A
AU  - Powell KA
FAU - White, Kathryn E
AU  - White KE
FAU - Yip, Wanfen
AU  - Yip W
FAU - Hogan, Vanessa
AU  - Hogan V
FAU - Hollins, Andrew J
AU  - Hollins AJ
FAU - Davies, Jennifer R
AU  - Davies JR
FAU - Piechota, Malgorzata
AU  - Piechota M
FAU - Brownstein, David G
AU  - Brownstein DG
FAU - Moat, Stuart J
AU  - Moat SJ
FAU - Nichols, Philip P
AU  - Nichols PP
FAU - Wride, Michael A
AU  - Wride MA
FAU - Boulton, Michael E
AU  - Boulton ME
FAU - Votruba, Marcela
AU  - Votruba M
LA  - eng
GR  - G0500790/MRC_/Medical Research Council/United Kingdom
GR  - G0700949/MRC_/Medical Research Council/United Kingdom
GR  - G108/523/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Glutarates)
RN  - 0 (OPA3 protein, human)
RN  - 0 (Opa3 protein, mouse)
RN  - 0 (Proteins)
RN  - 5746-90-7 (3-methylglutaconic acid)
SB  - IM
MH  - Amino Acid Metabolism, Inborn Errors/genetics
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Brain/ultrastructure
MH  - Cardiomyopathy, Dilated/genetics/pathology
MH  - *Disease Models, Animal
MH  - Glutarates/urine
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Molecular Sequence Data
MH  - *Mutation, Missense
MH  - Optic Atrophy, Autosomal Dominant/*genetics/physiopathology
MH  - Optic Nerve/ultrastructure
MH  - Phenotype
MH  - Point Mutation
MH  - Proteins/*genetics
MH  - Retinal Ganglion Cells/pathology
MH  - Reverse Transcriptase Polymerase Chain Reaction/methods
MH  - Spinal Cord/ultrastructure
MH  - Syndrome
MH  - Transcription, Genetic
MH  - Visual Acuity
EDAT- 2008/01/29 09:00
MHDA- 2008/04/24 09:00
CRDT- 2008/01/29 09:00
PHST- 2008/01/29 09:00 [pubmed]
PHST- 2008/04/24 09:00 [medline]
PHST- 2008/01/29 09:00 [entrez]
AID - 131/2/368 [pii]
AID - 10.1093/brain/awm333 [doi]
PST - ppublish
SO  - Brain. 2008 Feb;131(Pt 2):368-80. doi: 10.1093/brain/awm333.