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. PMID: 20673863 [PubMed - indexed for MEDLINE]PMCID: PMC2917711Free PMC Article Images from this publication.See all images (4) Free text Figure1 Genetic Analyses of Patients with Syndromic Overgrowth(A) The figure shows the Ensembl display of the 19p13.2p13.3 region. Position of nonoverlapping NFIX deletions detected in patients Aand B are represented by squares. For patient A, we found the proximal and distal breakpoints at 12 898 751 and 13 0... Distinct Effects of Allelic NFIX Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome Am J Hum Genet. 2010 August 13;87(2):189-198. Figure2 Front Views of the Three Overgrowth Syndrome PatientsNote the high forehead, long narrow face (patients A and C), and slender habitus. Distinct Effects of Allelic NFIX Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome Am J Hum Genet. 2010 August 13;87(2):189-198. Figure3 Pictures and Hand and Foot X-Rays of Patients with Marshall-Smith SyndromeFacial features of the nine patients with Marshall-Smith syndrome (A–I) and hand X-rays at 1 year (J) and 4 years (K) of age and foot X-rays at 1 year of age (L). Note thehigh forehead, proptosis, underdeveloped midface, the ... Distinct Effects of Allelic NFIX Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome Am J Hum Genet. 2010 August 13;87(2):189-198. Figure4 Pattern of NFIX Expression in Early Human Development and Fetal Epiphyseal Growth Plate(A–G) Adjacent sections of human embryos and fetuses treated with antisense (A–C, E–G) or with control sense (D) riboprobes.(A) Carnegie stage 17 (CS17) human embryo section.(B–D) CS19 human embryo sections.(E) Fronta... Distinct Effects of Allelic NFIX Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome Am J Hum Genet. 2010 August 13;87(2):189-198.