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.

Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features

“…7 Thus missense mutations in the DNAbinding/dimerization domain, which may lead to loss of transcriptional regulation by NFIX protein, could cause Sotos-like syndrome in two patients. Many clinical features including tall statue, mental retardation, speech delay and high forehead are shared between our patients and three patients reported by Malan et al 6 with NFIX abnormalities. The recognizable difference is autistic traits.…”

“…Because NFIX mutations could cause both Marshall-Smith syndrome and Sotos-like features, 6 it is great concern to which of them two patients with missense mutations could be classified. Main clinical features of Sotos syndrome are childhood overgrowth including tall stature and/or macrocephaly, characteristic face and mental retardation.…”

“…In addition, a nonsense mutation in NFIX was identified in one patient with Sotos-like features. 6 Interestingly, frameshift and donor-splice site mutations were also identified in Marshall-Smith syndrome (MIM 602535) that is osteochondysplasia syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation and unusual facial features. 7 Therefore, NFIX mutations could cause either Sotos-like features or Marshall-Smith syndrome.…”

“…Whereas the transcripts possessing the nonsense mutation in a patient with Sotos-like features suffered from the nonsense-mediated mRNA decay, transcripts of mutated alleles (by a donor-spice site and two frameshift mutations) in patients with Marshall-Smith syndrome escaped from the nonsense-mediated mRNA decay surveillance and could be translated, suggesting that haploinsufficiency of NFIX leads to Sotos-like features and dominant-negative effects of the truncated NFIX proteins cause Marshall-Smith syndrome. 6 In this study, we screened for NFIX mutations in 48 Japanese patients who were suspected as Sotos syndrome, but showed neither deletions nor mutations in NSD1. Detailed genetic and clinical data are presented.…”

Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes

“…The only known causes for this syndrome are de novo mutations in the NFIX gene, recently reported by Malan et al (2). In addition, some mutations in NFIX gene can cause a Sotoslike phenotype, in NSD1 mutation-negative patients, an overgrowth disorder with a less severe phenotype than MSS.…”