RESUMEN
The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division.
Asunto(s)
División Celular Asimétrica/fisiología , Polaridad Celular/fisiología , Proteínas de la Membrana/genética , Microcefalia/virología , Neuronas/metabolismo , Proteínas Nucleares/genética , Animales , División Celular , Drosophila melanogaster/metabolismo , Humanos , Mutación , Células-Madre Neurales/metabolismo , Células-Madre Neurales/virología , Neuronas/citología , Virus ZikaRESUMEN
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
Asunto(s)
Trastorno Autístico/diagnóstico , Trastorno Autístico/genética , Exoma/genética , Estudio de Asociación del Genoma Completo/métodos , Adolescente , Animales , Células Cultivadas , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Linaje , Ratas , Análisis de Secuencia de ADN/métodos , Adulto JovenRESUMEN
Mutations in the ASPM gene at the MCPH5 locus are expected to be the most common cause of human autosomal recessive primary microcephaly (MCPH), a condition in which there is a failure of normal fetal brain development, resulting in congenital microcephaly and mental retardation. We have performed the first comprehensive mutation screen of the 10.4-kb ASPM gene, identifying all 19 mutations in a cohort of 23 consanguineous families. Mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5-11 SDs below normal) and of mental retardation (mild to severe) but appeared independent of mutation position.
Asunto(s)
Encéfalo/anomalías , Encéfalo/metabolismo , Microcefalia/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Secuencia de Aminoácidos , Secuencia de Bases , Encéfalo/patología , Cromosomas Humanos Par 1/genética , Codón sin Sentido/genética , Consanguinidad , Análisis Mutacional de ADN , Exones/genética , Mutación del Sistema de Lectura/genética , Genes Recesivos/genética , Haplotipos/genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Intrones/genética , Masculino , Microcefalia/complicaciones , Microcefalia/patología , Repeticiones de Microsatélite/genética , Pakistán , Fenotipo , Polimorfismo Genético/genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. Humans with autosomal recessive primary microcephaly (MCPH) show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation. Genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex. Here we show that the most common cause of MCPH is homozygous mutation of ASPM, the human ortholog of the Drosophila melanogaster abnormal spindle gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. The mouse gene Aspm is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis. Notably, the predicted ASPM proteins encode systematically larger numbers of repeated 'IQ' domains between flies, mice and humans, with the predominant difference between Aspm and ASPM being a single large insertion coding for IQ domains. Our results and evolutionary considerations suggest that brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells.
