The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations.
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
Yasukazu
Y
Yamada
Noriko
N
Nomura
Kenichiro
K
Yamada
Mari
M
Matsuo
Yuka
Y
Suzuki
Kiyoko
K
Sameshima
Reiko
R
Kimura
Yuto
Y
Yamamoto
Daisuke
D
Fukushi
Yayoi
Y
Fukuhara
Naoko
N
Ishihara
Eriko
E
Nishi
George
G
Imataka
Hiroshi
H
Suzumura
Shin-Ichiro
S
Hamano
Kenji
K
Shimizu
Mie
M
Iwakoshi
Kazunori
K
Ohama
Akira
A
Ohta
Hiroyuki
H
Wakamoto
Mitsuharu
M
Kajita
Kiyokuni
K
Miura
Kenji
K
Yokochi
Kenjiro
K
Kosaki
Tatsuo
T
Kuroda
Rika
R
Kosaki
Yoko
Y
Hiraki
Kayoko
K
Saito
Seiji
S
Mizuno
Kenji
K
Kurosawa
Nobuhiko
N
Okamoto
Nobuaki
N
Wakamatsu
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D019066:Facies; D005260:Female; D016368:Frameshift Mutation; D015870:Gene Expression; D056726:Genetic Association Studies; D006627:Hirschsprung Disease / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D007564:Japan; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D015995:Prevalence; D055550:Protein Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000074165:Zinc Finger E-box Binding Homeobox 2
D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2
Mowat-Wilson syndrome; ZEB2; frameshift mutation; nonsense mutation