Distinct Effects of Allelic NFIX Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome

作者：Malan Valerie; Rajan Diana; Thomas Sophie; Shaw Adam C; Picard Helene Louis Dit; Layet Valerie; Till Marianne; van Haeringen Arie; Mortier Geert; Nampoothiri Sheela; Puseljic Silvija; Legeai Mallet Laurence; Carter Nigel P; Vekemans Michel; Munnich Arnold; Hennekam Raoul C; Colleaux Laurence^*; Cormier Daire Valerie

来源：American Journal of Human Genetics, 2010, 87(2): 189-198.

DOI：10.1016/j.ajhg.2010.07.001

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.

• 出版日期2010-8-13
• 单位河北医科大学