Truncating mutation in NFIA causes brain malformation and urinary tract defects

Negishi, Yutaka; Miya, Fuyuki; Hattori, Ayako; Mizuno, Kentaro; Hori, Ikumi; Ando, Nobutoshi; Okamoto, Nobuhiko; Kato, Mitsuhiro; Tsunoda, Tatsuhiko; Yamasaki, Mami; Kanemura, Yonehiro; Kosaki, Kenjiro; Saitoh, Shinji

doi:10.1038/hgv.2015.7

Cited by 26 publications

(28 citation statements)

References 18 publications

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“…Genomic DNA was captured using the SureSelect XT Human All Exon V5 capture library (Agilent Technologies, Santa Clara, CA, USA), and sequenced using the Illumina HiSeq 2000 (Illumina, San Diego, CA, USA) with 100 bp paired-end reads. Exome data processing, variant calling and variant annotation were performed as described previously [15]. …”

Section: Methodsmentioning

confidence: 99%

A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly

et al. 2017

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BackgroundConstitutive activation of the PI3K-AKT-mTOR pathway (mTOR pathway) underlies megalencephaly in many patients. Yet, prevalence of the involvement of the PI3K-AKT-mTOR pathway in patients with megalencephaly remains to be elucidated, and molecular diagnosis is challenging. Here, we have successfully established a combination of genetic and biochemical methods for diagnosis of mTOR pathway-associated megalencephaly, and have attempted to delineate the clinical characteristics of the disorder.MethodsThirteen patients with an increased head circumference and neurological symptoms participated in the study. To evaluate the activation of the mTOR pathway, we performed western blot analysis to determine the expression levels of phosphorylated S6 ribosomal protein (phospho-S6 protein) in lymphoblastoid cell lines from 12 patients. Multiplex targeted sequencing analysis for 15 genes involved in the mTOR pathway was performed on 12 patients, and whole-exome sequencing was performed on one additional patient. Clinical features and MRI findings were also investigated.ResultsWe identified pathogenic mutations in six (AKT3, 1 patient; PIK3R2, 2 patients; PTEN, 3 patients) of the 13 patients. Increased expression of phospho-S6 protein was demonstrated in all five mutation-positive patients in whom western blotting was performed, as well as in three mutation-negative patients. Developmental delay, dysmorphic facial features were observed in almost all patients. Syndactyly/polydactyly and capillary malformations were not observed, even in patients with AKT3 or PIK3R2 mutations. There were no common phenotypes or MRI findings among these patients.ConclusionsA combination of genetic and biochemical methods successfully identified mTOR pathway involvement in nine of 13 (approximately 70%) patients with megalencephaly, indicating a major contribution of the pathway to the pathogenesis of megalencephaly. Our combined approach could be useful to identify patients who are suitable for future clinical trials using an mTOR inhibitor.

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Section: Methodsmentioning

confidence: 99%

A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly

et al. 2017

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“…Deletions of chromosome 1p32p31 (chromosome 1p32p31 deletion syndrome [MIM: 613735]) as well as deletions or sequence variants of NFIA lead to a phenotype with developmental delay, macrocephaly, ID, dysgenesis of the corpus callosum, ventriculomegaly or congenital hydrocephalus, and craniofacial dysmorphisms. [10][11][12][13][14][15][16][17][18][19] Haploinsufficiency of NFIX causes Sotos syndrome 2 or Malan syndrome (MIM: 614753), which is characterized by developmental delay, macrocephaly, ID, postnatal overgrowth, and mild craniofacial anomalies. [20][21][22][23][24][25][26] In addition, specific sequence variants affecting the 3 0 region of NFIX cause Marshall-Smith syndrome (MSS) (MIM: 602535), a more severe phenotype with severe intellectual disability, progressive dysostosis, respiratory difficulties, and a characteristic facial dysmorphism, and is presumably a result of a dominant-negative mechanism.…”

Section: Introductionmentioning

confidence: 99%

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Schanze

Bunt

Lim

et al. 2018

The American Journal of Human Genetics

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The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

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“…Nuclear factor I-A (NFIA) and nuclear factor I-B (NFIB) are important for normal cortical development, as knockout of either Nfia or Nfib in mice results in very similar brain phenotypes, including dysgenesis of the corpus callosum, the disruption of midline fusion, enlarged ventricles and malformation of the hippocampus (Das Neves et al, 1999;Gobius et al, 2016;Piper et al, 2010;Shu et al, 2003;SteelePerkins et al, 2005). Similarly, mutations or deletions of NFIA and NFIB in human patients with intellectual disability are associated with severe brain phenotypes, including dysgenesis of the corpus callosum, macrocephaly and enlarged ventricles Koehler et al, 2010;Lu et al, 2007;Negishi et al, 2015;Sajan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Combined allelic dosage of Nfia and Nfib regulates cortical development

Bunt

Osinski

Lim

et al. 2017

Brain and Neuroscience Advances

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Background: Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate similar biological processes, as their expression patterns, regulation of target genes and individual knockout phenotypes overlap. We hypothesised that the combined allelic loss of Nfia and Nfib would culminate in more severe defects in the cerebral cortex than loss of a single member. Methods: We combined immunofluorescence, co-immunoprecipitation, gene expression analysis and immunohistochemistry on knockout mouse models to investigate whether nuclear factor I A and nuclear factor I B function similarly and whether increasing allelic loss of Nfia and Nfib caused a more severe phenotype. Results: We determined that the biological functions of nuclear factor I A and nuclear factor I B overlap during early cortical development. These proteins are co-expressed and can form heterodimers in vivo. Differentially regulated genes that are shared between Nfia and Nfib knockout mice are highly enriched for nuclear factor I binding sites in their promoters and are associated with neurodevelopment. We found that compound heterozygous deletion of both genes resulted in a cortical phenotype similar to that of single homozygous Nfia or Nfib knockout embryos. This was characterised by retention of the interhemispheric fissure, dysgenesis of the corpus callosum and a malformed dentate gyrus. Double homozygous knockout of Nfia and Nfib resulted in a more severe phenotype, with increased ventricular enlargement and decreased numbers of differentiated glia and neurons. Conclusion: In the developing cerebral cortex, nuclear factor I A and nuclear factor I B share similar biological functions and function additively, as the combined allelic loss of these genes directly correlates with the severity of the developmental brain phenotype.

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Truncating mutation in NFIA causes brain malformation and urinary tract defects

Cited by 26 publications

References 18 publications

A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly

A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Combined allelic dosage of Nfia and Nfib regulates cortical development

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