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Am J Hum Genet ; 104(2): 319-330, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639322


ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação Puntual , Fatores de Transcrição/genética , Alelos , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Camundongos , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
JAMA Neurol ; 75(3): 328-341, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29340569


Importance: Late-onset Alzheimer disease (AD) is highly heritable. Genome-wide association studies have identified more than 20 AD risk genes. The precise mechanism through which many of these genes are associated with AD remains unknown. Objective: To investigate the association of the top 20 AD risk variants with brain amyloidosis. Design, Setting, and Participants: This study analyzed the genetic and florbetapir F 18 data from 322 cognitively normal control individuals, 496 individuals with mild cognitive impairment, and 159 individuals with AD dementia who had genome-wide association studies and 18F-florbetapir positron emission tomographic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective, observational, multisite tertiary center clinical and biomarker study. This ongoing study began in 2005. Main Outcomes and Measures: The study tested the association of AD risk allele carrier status (exposure) with florbetapir mean standard uptake value ratio (outcome) using stepwise multivariable linear regression while controlling for age, sex, and apolipoprotein E ε4 genotype. The study also reports on an exploratory 3-dimensional stepwise regression model using an unbiased voxelwise approach in Statistical Parametric Mapping 8 with cluster and significance thresholds at 50 voxels and uncorrected P < .01. Results: This study included 977 participants (mean [SD] age, 74 [7.5] years; 535 [54.8%] male and 442 [45.2%] female) from the ADNI-1, ADNI-2, and ADNI-Grand Opportunity. The adenosine triphosphate-binding cassette subfamily A member 7 (ABCA7) gene had the strongest association with amyloid deposition (χ2 = 8.38, false discovery rate-corrected P < .001), after apolioprotein E ε4. Significant associations were found between ABCA7 in the asymptomatic and early symptomatic disease stages, suggesting an association with rapid amyloid accumulation. The fermitin family homolog 2 (FERMT2) gene had a stage-dependent association with brain amyloidosis (FERMT2 × diagnosis χ2 = 3.53, false discovery rate-corrected P = .05), which was most pronounced in the mild cognitive impairment stage. Conclusions and Relevance: This study found an association of several AD risk variants with brain amyloidosis. The data also suggest that AD genes might differentially regulate AD pathologic findings across the disease stages.

Am J Hum Genet ; 102(1): 44-57, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29276004


Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.

Alzheimers Dement (Amst) ; 5: 53-66, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28054028


INTRODUCTION: We analyzed the effects of the top 20 Alzheimer disease (AD) risk genes on gray-matter density (GMD) and metabolism. METHODS: We ran stepwise linear regression analysis using posterior cingulate hypometabolism and medial temporal GMD as outcomes and all risk variants as predictors while controlling for age, gender, and APOE ε4 genotype. We explored the results in 3D using Statistical Parametric Mapping 8. RESULTS: Significant predictors of brain GMD were SLC24A4/RIN3 in the pooled and mild cognitive impairment (MCI); ZCWPW1 in the MCI; and ABCA7, EPHA1, and INPP5D in the AD groups. Significant predictors of hypometabolism were EPHA1 in the pooled, and SLC24A4/RIN3, NME8, and CD2AP in the normal control group. DISCUSSION: Multiple variants showed associations with GMD and brain metabolism. For most genes, the effects were limited to specific stages of the cognitive continuum, indicating that the genetic influences on brain metabolism and GMD in AD are complex and stage dependent.

J Educ Stud Placed Risk ; 20(1-2): 141-168, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26709340


The Los Angeles Unified School District (LAUSD) serves a large majority of socioeconomically disadvantaged students who are struggling academically and are underprepared for high school graduation and college. This article describes the partnership between LAUSD and the Los Angeles Education Research Institute, and how this collaboration endeavors to produce accessible and high-quality research to inform pressing problems of practice. The article also presents findings from an ongoing partnership research project analyzing a district policy focused on improving college readiness by aligning high school graduation and college-eligibility requirements. In a cohort that went through high school before the policy became mandatory for all students, less than 1/5 of all students (and 30% of graduates) met the college eligibility criteria. Our findings indicate that academic and behavioral indicators from 8th and 9th grade can help identify for possible intervention students who are not on track to meet these new graduation requirements.

Child Dev ; 73(4): 1283-309, 2002 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12146748


This study assessed some ways in which schools, neighborhoods, nuclear families, and friendship groups jointly contribute to positive change during early adolescence. For each context, existing theory was used to develop a multiattribute index that should promote successful development. Descriptive analyses showed that the four resulting context indices were only modestly intercorrelated at the individual student level (N = 12,398), but clustered more tightly at the school and neighborhood levels (N = 23 and 151 respectively). Only for aggregated units did knowing the developmental capacity of any one context strongly predict the corresponding capacity of the other contexts. Analyses also revealed that each context facilitated individual change in a success index that tapped into student academic performance, mental health, and social behavior. However, individual context effects were only modest in size over the 19 months studied and did not vary much by context. The joint influence of all four contexts was cumulatively large, however, and because it was generally additive in form, no constellation of contexts was identified whose total effect reliably surpassed the sum of its individual context main effects. These results suggest that achieving significant population changes in multidimensional student growth during early adolescence most likely requires both theory and interventions that are explicitly pan-contextual.

Escolaridade , Amigos/psicologia , Núcleo Familiar , Grupo Associado , Desenvolvimento da Personalidade , Características de Residência , Meio Social , Adolescente , Feminino , Humanos , Delinquência Juvenil/psicologia , Masculino , Maryland , Fatores de Risco , Apoio Social , Socialização , Fatores Socioeconômicos , Transtornos Relacionados ao Uso de Substâncias/psicologia