Publication Type:

Journal Article

Source:

American Journal of Human Genetics, Volume 87, Number 2, p.189-198 (2010)

URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-77955576632&partnerID=40&md5=33087eb0592e0da7d0a26185fbf59b01

Keywords:

Abnormalities, adolescent, adult, allele, Alleles, article, Base Sequence, bone demineralization, bone development, brain development, child, Chromosomes, codon, comparative genomic hybridization, DNA Mutational Analysis, embryo, facies, failure to thrive, female, fetus, frameshift mutation, gene deletion, Gene Expression Regulation, gene mutation, Genetic Testing, human, human tissue, Humans, In Situ Hybridization, kyphoscoliosis, major clinical study, male, malformation syndrome, marshall smith syndrome, Messenger, Molecular Sequence Data, mouse, Multiple, Mus, Mutation, newborn, NFI Transcription Factors, nonhuman, Nonsense, nonsense mediated mRNA decay, nuclear factor, nuclear factor I, nuclear factor ix, osteopenia, Pair 19, phenotype, priority journal, protein expression, protein function, respiratory failure, Reverse Transcriptase Polymerase Chain Reaction, RNA, RNA splicing, RNA Stability, Sotos syndrome, spine malformation, Syndrome, unclassified drug, weight gain

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. © 2010 The American Society of Human Genetics.

Notes:

cited By (since 1996)13

Cite this Research Publication

Va Malan, Rajan, Db, Thomas, Sa, Shaw, A. Cc, Picard, HaLouis Dit, Layet, Vd, Till, Me, Van Haeringen, Af, Mortier, Gg, Nampoothiri, Sh, Pušeljić, Si, Legeai-Mallet, La, Carter, N. Pb, Vekemans, Ma, Munnich, Aa, Hennekam, R. Cj, Colleaux, La, and Cormier-Daire, Va, “Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a sotos-like or a Marshall-Smith Syndrome”, American Journal of Human Genetics, vol. 87, pp. 189-198, 2010.