Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome.
BACKGROUND
Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes.


RESULTS
DNA was isolated from 2 families and 3 individuals with isolated LVNC or LVNC with congenital heart disease (CHD), as well as 4 families with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. In 1 family with LVNC and CHD, a C-->T mutation was identified at nucleotide 362 of alpha-dystrobrevin, changing a proline to leucine (P121L). Mutations in G4.5 were identified in 2 families with isolated LVNC: a missense mutation in exon 4 (C118R) in 1 and a splice donor mutation (IVS10+2T-->A) in intron 10 in the other. In a family with cardiomyopathies ranging from BTHS or fatal infantile cardiomyopathy to asymptomatic DCM, a splice acceptor mutation in exon 2 of G4.5 (398-2 A-->G) was identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop codon after amino acid 41, was identified in a sporadic case of BTHS.


CONCLUSIONS
These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, alpha-dystrobrevin, identified in LVNC associated with CHD. In addition, these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.
Ichida
F
F
Department of Pediatrics, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Tsubata
S
S
Bowles
K R
KR
Haneda
N
N
Uese
K
K
Miyawaki
T
T
Dreyer
W J
WJ
Messina
J
J
Li
H
H
Bowles
N E
NE
Towbin
J A
JA
D000217:Acyltransferases; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D049029:Dystrophin-Associated Proteins; D005192:Family Health; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors
D003598:Cytoskeletal Proteins; D049029:Dystrophin-Associated Proteins; D008565:Membrane Proteins; D011506:Proteins; D014157:Transcription Factors; C098885:dystrobrevin; D004247:DNA; D000217:Acyltransferases; C108675:TAFAZZIN protein, human