ABSTRACT
Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome (PWS/AS) critical region have been described in individuals with autism. Maternal duplications and linkage disequilibrium in families with autism suggest the existence of a susceptibility locus at 15q11-q13. Here, we describe a 6-year-old girl diagnosed with autism, developmental delay, and delayed expressive and receptive language. The karyotype was designated de novo 47, XX, idic(15)(q13). Fluorescence in situ hybridization (FISH) and molecular analysis with 15q11-q13 markers revealed an additional copy of the region being of maternal origin. Duplication of the 15q11-q13 segment represents the most consistent known chromosomal abnormality reported in association with autism. This present case report reinforces the hypothesis that additional copies of this chromosome segment are causally related to autism.
Subject(s)
Autistic Disorder/genetics , Chromosomes, Human, Pair 15/genetics , Developmental Disabilities/genetics , Language Development Disorders/genetics , Uniparental Disomy/diagnosis , Uniparental Disomy/genetics , Alleles , Angelman Syndrome/diagnosis , Angelman Syndrome/genetics , Autistic Disorder/diagnosis , Child , Chromosome Banding , Chromosome Mapping , Developmental Disabilities/diagnosis , Female , Gene Duplication , Genetic Markers/genetics , Genotype , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Language Development Disorders/diagnosis , Microsatellite Repeats , Personality Assessment , Prader-Willi Syndrome/diagnosis , Prader-Willi Syndrome/genetics , Statistics as TopicABSTRACT
The existence of transcripts that span two adjacent, independent genes is considered rare in the human genome. This study characterizes a novel human fusion gene named IQCJ-SCHIP1. IQCJ-SCHIP1 is the longest isoform of a complex transcriptional unit that bridges two separate genes that encode distinct proteins, IQCJ, a novel IQ motif containing protein and SCHIP1, a schwannomin interacting protein that has been previously shown to interact with the Neurofibromatosis type 2 (NF2) protein. IQCJ-SCHIP1 is located on the chromosome 3q25 and comprises a 1692-bp transcript encompassing 11 exons spanning 828kb of the genomic DNA. We show that IQCJ-SCHIP1 mRNA is highly expressed in the brain. Protein encoded by the IQCJ-SCHIP1 gene was localized to cytoplasm and actin-rich regions and in differentiated PC12 cells was also seen in neurite extensions.
Subject(s)
Calmodulin-Binding Proteins/genetics , Open Reading Frames/genetics , Recombinant Fusion Proteins/genetics , Transcription Factors/genetics , Transcriptional Activation/genetics , Amino Acid MotifsABSTRACT
Microsomal cytochrome P450 reductase catalyzes the one-electron transfer from NADPH via FAD and FMN to various electron acceptors, such as cytochrome P450s or to some anti-cancer quinone drugs. This results in generation of free radicals and toxic oxygen metabolites, which can contribute to the cytotoxicity of these compounds. Recently, a cytosolic NADPH-dependent flavin reductase, NR1, has been described which is highly homologous to the microsomal cytochrome P450 reductase. In this study, we show that over-expression of NR1 in human embryonic kidney cells enhances the cytotoxic action of the model quinone, menadione. Furthermore, we show that a novel human histidine triad protein DCS-1, which is expressed together with NR1 in many tissues, can significantly reduce menadione-induced cytotoxicity in these cells. We also show that DCS-1 binds NF1 and directly modulates its activity. These results suggest that NR1 may play a role in carcinogenicity and cell death associated with one-electron reductions.
Subject(s)
Cell Survival/physiology , Flavoproteins/metabolism , Kidney/cytology , Kidney/metabolism , N-Glycosyl Hydrolases/metabolism , Oxidoreductases/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Vitamin K 3/administration & dosage , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Flavoproteins/genetics , Humans , Kidney/drug effects , N-Glycosyl Hydrolases/genetics , Oxidoreductases/genetics , Saccharomyces cerevisiae Proteins/genetics , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
Specific language impairment (SLI) is defined as failure to acquire normal language skills despite adequate intelligence and environmental stimulation. Although SLI disorders are often heritable, the genetic basis is likely to involve a number of risk factors. This study describes a 7-year-old girl carrying an inherited paracentric inversion of the long arm of chromosome 3 [46XX, inv(3)(q25.32-q29)] having clinically defined expressive and receptive language delay. Fluorescence in situ hybridization (FISH) with locus-specific bacterial artificial chromosome clones (BACs) as probes was used to characterize the inverted chromosome 3. The proximal and distal inversion breakpoint was found to reside between markers D3S3692/D3S1553 and D3S3590/D3S2305, respectively. ATP13A4, a novel gene coding for a cation-transporting P-type ATPase, was found to be disrupted by the distal breakpoint. The ATP13A4 gene was shown to comprise a 3591-bp transcript encompassing 30 exons spanning 152 kb of the genomic DNA. This study discusses the characterization of ATP13A4 and its possible involvement in speech-language disorder.
