RESUMO
Two siblings from a consanguineous Egyptian marriage showed an identical phenotype of cortical lissencephaly with cerebellar hypoplasia, severe epilepsy, and mental retardation. Examination of karyotype revealed 46, t(7;12)(q22;p13)mat (7;12)(q22;p13)pat in both affected children, suggesting a homozygous reciprocal balanced translocation. Each healthy parent was a carrier of the balanced translocation in the heterozygous state, suggesting homozygous disruption of a gene involved in brain development. There were early spontaneous abortions in this family, as would be expected from transmission of an unbalanced chromosome. A disruption of RELN at 7q22.1 with absence of encoded protein was identified. This is the first demonstration that such rare homozygous translocations can be used to identify recessive disease gene mutations.
Assuntos
Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Genes Recessivos , Mutação , Proteínas do Tecido Nervoso/genética , Serina Endopeptidases/genética , Translocação Genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Encéfalo/anormalidades , Encefalopatias/genética , Pré-Escolar , Bandeamento Cromossômico , Epilepsia/genética , Feminino , Homozigoto , Humanos , Deficiência Intelectual/genética , Masculino , Linhagem , Receptores Proteína Tirosina Quinases/genética , Proteína ReelinaRESUMO
Cytogenetic imbalances are increasingly being realized as causes of autism. Here, we report a de novo translocation between the short arms of chromosomes 15 and 16 in a female with autism, epilepsy, and global developmental delay. FISH analysis identified a cryptic deletion of approximately 160 kb at the boundary of the first exon and first intron of the 1.7 Mb ataxin-2 binding protein-1 (A2BP1) gene, also called FOX1. Quantitative real time PCR (Q-PCR) analysis verified a deletion of exon 1 in the 5' promoter region of the A2BP1 gene. Reverse transcription PCR (qRT-PCR) showed reduced mRNA expression in the individual's lymphocytes, demonstrating the functional consequence of the deletion. A2BP1 codes for a brain-expressed RNA binding or splicing factor. Because of emerging evidence in the role of RNA processing and gene regulation in pervasive developmental disorders, we performed further screening of A2BP1 in additional individuals with autism from the Autism Genetics Resource Exchange (AGRE) collection. Twenty-seven SNPs were genotyped across A2BP1 in 206 parent-child trios and two regions showed association at P < or = 0.008 level. No additional deletions or clear mutations were identified in 88 probands by re-sequencing of all exons and surrounding intronic regions or quantitative PCR (Q-PCR) of exon 1. Although only nominal association was observed, and no obvious causal mutations were identified, these results suggest that A2BP1 may affect susceptibility or cause autism in a subset of patients. Further investigations in a larger sample may provide additional information regarding the involvement of this gene in the autistic phenotype.
Assuntos
Transtorno Autístico/genética , Proteínas de Ligação a RNA/genética , Pré-Escolar , Cromossomos Humanos Par 15 , Cromossomos Humanos Par 7 , Análise Citogenética , Epilepsia/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/genética , Fatores de Processamento de RNA , Translocação GenéticaRESUMO
Mice homozygous for the dreher (dr) mutation are characterized by pigmentation and skeletal abnormalities and striking behavioral phenotypes, including ataxia, vestibular deficits, and hyperactivity. The ataxia is associated with a cerebellar malformation that is remarkably similar to human Dandy-Walker malformation. Previously, positional cloning identified mutations in LIM homeobox transcription factor 1 alpha gene (Lmx1a) in three dr alleles. Two of these alleles, however, are extinct and unavailable for further analysis. In this article we report a new spontaneous dr allele and describe the Lmx1a mutations in this and six additional dr alleles. Strikingly, deletion null, missense, and frameshift mutations in these alleles all cause similar cerebellar malformations, suggesting that all dr mutations analyzed to date are null alleles.
Assuntos
Análise Mutacional de DNA/métodos , Proteínas de Homeodomínio/genética , Mutação , Alelos , Sequência de Aminoácidos , Animais , Cerebelo/anormalidades , Cerebelo/citologia , Síndrome de Dandy-Walker/genética , Modelos Animais de Doenças , Proteínas com Homeodomínio LIM , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Fatores de TranscriçãoRESUMO
The telomeric region of chromosome 9p is paralogous to the pericentromeric regions of chromosome 9 as well as to 2q13, the site of an ancestral telomere-telomere fusion. These paralogous regions span approximately 200 kb and contain seven transcriptional units, including the previously identified CBWD, FOXD4, PGM5, F379, CXYorf1, and two human Unigene clusters, Hs.115173 and Hs.189160. Within these gene duplicates, the number of expressed paralogous loci varies, from one in PGM5 to all three in CBWD and Hs.115173. FOXD4 shows the most dramatic changes among its paralogs. Two independent insertion/deletion changes created four different carboxy ends of these intronless genes, two of which are within the 2q13 locus. A comparison of KA/KS values among functional paralogs shows these genes evolved rapidly in primates. This study shows the importance of paralogous regions in the generation of transcriptional diversity and highlights the significance that large-scale telomeric duplication may play in this process.