Nuclear Factor I X Deficiency Causes Brain Malformation and Severe Skeletal Defects

Driller, Katrin; Pagenstecher, Axel; Uhl, Markus; Omran, Heymut; Berlis, Ansgar; Gründer, Albert; Sippel, Albrecht E.

doi:10.1128/mcb.02293-06

Cited by 126 publications

(151 citation statements)

References 73 publications

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“…We note that mice deficient in Nfix function show, in addition to brain abnormalities, a kyphotic deformation of the spine and impairment of endochondral ossification in the vertebrae and femur. 15,16 There have been no reports of neoplasia in the condition to date. The small number of cases reported to date hinders identification of genotype-phenotype correlations for NFIX.…”

Section: Molecular Resultsmentioning

confidence: 99%

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

et al. 2014

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De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.

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Section: Molecular Resultsmentioning

confidence: 99%

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

et al. 2014

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“…29 Nfix-deficient mice show enlargement of the lateral and third brain ventricles and partial agenesis of the corpus callosum; in addition, they show kyphotic deformation of the spine and impaired endochondral ossification in the vertebrae and femur. 29 The case of Lysy et al 4 showed kyphosis, artogryphosis of lower limb craniosynostosys and moderate ventriculomegaly; 4 Auvin et al 5 reported advanced bone age. As our case 3 does not show any of these malformations, the phenotype associated with NFIX haploinsufficiency may occur with variable penetrance.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

et al. 2010

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We describe the detailed clinical and molecular characterization of three patients (aged 7, 8 4/12 and 31 years) with overlapping microdeletions in 19p13.12, extending to 19p13.13 in two cases. The patients share the following clinical features with a recently reported 10-year-old girl with a 19p13.12 microdeletion: mental retardation (MR), psychomotor and language delay, hearing impairment, brachycephaly, anteverted nares and ear malformations. All patients share a 359-kb deleted region in 19p13.12 harboring six genes (LPHN1, DDX39, CD97, PKN1, PTGER1 and GIPC1), several of which may be MR candidates because of their function and expression pattern. LPHN1 and PKN1 are the most appealing; LPHN1 for its interaction with Shank family proteins, and PKN1 because it is involved in a variety of functions in neurons, including cytoskeletal organization. Haploinsufficiency of GIPC1 may contribute to hearing impairment for its interaction with myosin VI. A behavioral phenotype was observed in all three patients; it was characterized by overactive disorder associated with MR and stereotyped movements (ICD10) in one patient and hyperactivity in the other two. As Ptger1-null mice show behavioral inhibition and impulsive aggression with defective social interaction, PTGER1 haploinsufficiency may be responsible for the behavioral traits observed in these patients.

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“…Nfix mutants present an overexpansion of the embryonic brain and a delay of hippocampal progenitor differentiation that are not seen in other Nfi mutants (Driller et al 2007;Campbell et al 2008;Heng et al 2012b). Moreover, manipulation of Nfia expression alongside that of Nfix in NS cells shows that the two genes have different activities in the cells, and Nfia does not have a prominent role in the regulation of quiescence (B Martynoga, unpubl.).…”

Section: Nfix Targets Cell Adhesion and Ecm Genes To Promote Ns Cell mentioning

confidence: 99%

Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence

Martynoga¹,

et al. 2013

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The majority of neural stem cells (NSCs) in the adult brain are quiescent, and this fraction increases with aging. Although signaling pathways that promote NSC quiescence have been identified, the transcriptional mechanisms involved are mostly unknown, largely due to lack of a cell culture model. In this study, we first demonstrate that NSC cultures (NS cells) exposed to BMP4 acquire cellular and transcriptional characteristics of quiescent cells. We then use epigenomic profiling to identify enhancers associated with the quiescent NS cell state. Motif enrichment analysis of these enhancers predicts a major role for the nuclear factor one (NFI) family in the gene regulatory network controlling NS cell quiescence. Interestingly, we found that the family member NFIX is robustly induced when NS cells enter quiescence. Using genome-wide location analysis and overexpression and silencing experiments, we demonstrate that NFIX has a major role in the induction of quiescence in cultured NSCs. Transcript profiling of NS cells overexpressing or silenced for Nfix and the phenotypic analysis of the hippocampus of Nfix mutant mice suggest that NFIX controls the quiescent state by regulating the interactions of NSCs with their microenvironment.

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Nuclear Factor I X Deficiency Causes Brain Malformation and Severe Skeletal Defects

Cited by 126 publications

References 73 publications

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

Genotype–phenotype relationship in three cases with overlapping 19p13.12 microdeletions

Epigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescence

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