Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome.
By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, Nfix-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider NFIX as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice NFIX mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that NFIX is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on NMD.
Malan
Valérie
V
Département de Génétique, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris 75015, France.
Rajan
Diana
D
Thomas
Sophie
S
Shaw
Adam C
AC
Louis Dit Picard
Hélène
H
Layet
Valérie
V
Till
Marianne
M
van Haeringen
Arie
A
Mortier
Geert
G
Nampoothiri
Sheela
S
Puseljić
Silvija
S
Legeai-Mallet
Laurence
L
Carter
Nigel P
NP
Vekemans
Michel
M
Munnich
Arnold
A
Hennekam
Raoul C
RC
Colleaux
Laurence
L
Cormier-Daire
Valérie
V
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D005820:Genetic Testing; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D051839:NFI Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome
D018389:Codon, Nonsense; D051839:NFI Transcription Factors; D012333:RNA, Messenger