%0 Journal Article %J Neuron %D 2015 %T Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. %A Karaca, Ender %A Harel, Tamar %A Pehlivan, Davut %A Jhangiani, Shalini N %A Gambin, Tomasz %A Coban Akdemir, Zeynep %A Gonzaga-Jauregui, Claudia %A Erdin, Serkan %A Bayram, Yavuz %A Campbell, Ian M %A Hunter, Jill V %A Atik, Mehmed M %A Van Esch, Hilde %A Bo Yuan %A Wiszniewski, Wojciech %A Isikay, Sedat %A Yesil, Gozde %A Yuregir, Ozge O %A Tug Bozdogan, Sevcan %A Aslan, Huseyin %A Aydin, Hatip %A Tos, Tulay %A Aksoy, Ayse %A De Vivo, Darryl C %A Jain, Preti %A Geckinli, B Bilge %A Sezer, Ozlem %A Gul, Davut %A Durmaz, Burak %A Cogulu, Ozgur %A Ozkinay, Ferda %A Topcu, Vehap %A Candan, Sukru %A Cebi, Alper Han %A Ikbal, Mevlit %A Yilmaz Gulec, Elif %A Gezdirici, Alper %A Koparir, Erkan %A Ekici, Fatma %A Coskun, Salih %A Cicek, Salih %A Karaer, Kadri %A Koparir, Asuman %A Duz, Mehmet Bugrahan %A Kirat, Emre %A Fenercioglu, Elif %A Ulucan, Hakan %A Seven, Mehmet %A Guran, Tulay %A Elcioglu, Nursel %A Yildirim, Mahmut Selman %A Aktas, Dilek %A Alikaşifoğlu, Mehmet %A Ture, Mehmet %A Yakut, Tahsin %A Overton, John D %A Yuksel, Adnan %A Ozen, Mustafa %A Donna M Muzny %A Adams, David R %A Eric Boerwinkle %A Chung, Wendy K %A Richard A Gibbs %A Lupski, James R %K Brain %K Cohort Studies %K Databases, Genetic %K Female %K Gene Regulatory Networks %K Genetic Association Studies %K Genetic Variation %K Humans %K Male %K Mendelian Randomization Analysis %K Nervous System Diseases %K Pedigree %X

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

%B Neuron %V 88 %P 499-513 %8 2015 Nov 04 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/26539891?dopt=Abstract %R 10.1016/j.neuron.2015.09.048 %0 Journal Article %J Am J Hum Genet %D 2014 %T Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations. %A Rainger, Joe %A Pehlivan, Davut %A Johansson, Stefan %A Bengani, Hemant %A Sanchez-Pulido, Luis %A Williamson, Kathleen A %A Ture, Mehmet %A Barker, Heather %A Rosendahl, Karen %A Spranger, Jürgen %A Horn, Denise %A Meynert, Alison %A Floyd, James A B %A Prescott, Trine %A Anderson, Carl A %A Rainger, Jacqueline K %A Karaca, Ender %A Gonzaga-Jauregui, Claudia %A Jhangiani, Shalini %A Donna M Muzny %A Seawright, Anne %A Soares, Dinesh C %A Kharbanda, Mira %A Murday, Victoria %A Finch, Andrew %A Richard A Gibbs %A van Heyningen, Veronica %A Taylor, Martin S %A Yakut, Tahsin %A Knappskog, Per M %A Hurles, Matthew E %A Ponting, Chris P %A Lupski, James R %A Houge, Gunnar %A FitzPatrick, David R %K Adult %K Alleles %K Animals %K Anophthalmos %K Brain Diseases, Metabolic, Inborn %K Coloboma %K Corneal Opacity %K Exome %K Eye Proteins %K Female %K Gene Expression %K HEK293 Cells %K Heterozygote %K Homozygote %K Humans %K Intellectual Disability %K Intracellular Signaling Peptides and Proteins %K Male %K Mice %K Microcephaly %K Microphthalmos %K Mutation, Missense %K Pedigree %K Phenotype %K Protein Conformation %K Signal Transduction %X

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

%B Am J Hum Genet %V 94 %P 915-23 %8 2014 Jun 05 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/24906020?dopt=Abstract %R 10.1016/j.ajhg.2014.05.005