title: Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome.
abstract: 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.
authors.affiliation: Département de Génétique, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris 75015, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Malan
authors.forename: Diana
authors.initials: D
authors.lastname: Rajan
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Adam C
authors.initials: AC
authors.lastname: Shaw
authors.forename: Hélène
authors.initials: H
authors.lastname: Louis Dit Picard
authors.forename: Valérie
authors.initials: V
authors.lastname: Layet
authors.forename: Marianne
authors.initials: M
authors.lastname: Till
authors.forename: Arie
authors.initials: A
authors.lastname: van Haeringen
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Silvija
authors.initials: S
authors.lastname: Puseljić
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Carter
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: 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
chemical_list: D018389:Codon, Nonsense; D051839:NFI Transcription Factors; D012333:RNA, Messenger