Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features.
Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yuriko
Y
Yoneda
Hirotomo
H
Saitsu
Mayumi
M
Touyama
Yoshio
Y
Makita
Akie
A
Miyamoto
Keisuke
K
Hamada
Naohiro
N
Kurotaki
Hiroaki
H
Tomita
Kiyomi
K
Nishiyama
Yoshinori
Y
Tsurusaki
Hiroshi
H
Doi
Noriko
N
Miyake
Kazuhiro
K
Ogata
Kenji
K
Naritomi
Naomichi
N
Matsumoto
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D019066:Facies; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D051839:NFI Transcription Factors / Q000235:genetics*; D055503:Protein Multimerization / Q000235:genetics; D016415:Sequence Alignment; D058495:Sotos Syndrome / Q000235:genetics*; D055815:Young Adult
D051839:NFI Transcription Factors