Exploring the 7p22.1 chromosome as a candidate region for autism.

A high incidence of de novo chromosomal aberrations in a population of persons with autism suggests a causal relationship between certain chromosomal aberrations and the occurrence of autism. A previous study on a Tunisian boy carrying a t(7;16) translocation identified the 7p22.1 as a positional candidate region for autism on chromosome 7. The characterization of the chromosomal breakpoints helped us to identify new candidate regions on chromosome 16p11.2 which contain no known genes and the other one on 7p22.1 containing a portion of genes (NP 976327.1, RBAK, Q6NUR6 also called RNF216L and MMD2). We proposed Q6NUR6 (RNF216L) as a candidate gene for autism due to its vicinity to the translocation breakpoint on the chromosome derivative 7. Q6NUR6 is predicted to be an E3ubiquitin-ligase. Quantitative PCR demonstrates that Q6NUR6 gene has an ubiquitous expression and that it is strongly expressed in fetal and adult brain. The Q6NUR6 expression is increased in the patient blood cells in comparison to controls. This is the first report of Q6NUR6 gene (E3 ubiquitin ligase TRIAD3 EC 6.3.2) increasing blood levels in a patient with autism. It's probably caused by a position effect involving this gene and modifying its expression.

Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level.

BACKGROUND: Pathogenic mutations in the X-linked Neuroligin 4 gene (NLGN4X) in autism spectrum disorders (ASDs) and/or mental retardation (MR) are rare. However, nothing is known regarding a possible altered expression level of NLGN4X that would be caused by mutations in regulatory sequences. We investigated this issue by analyzing these regions in patients with ASDs and no mutation in the NLGN4X coding sequence. METHODS: We studied 96 patients who met all DSM-IV criteria for autism. The entire coding sequence and the regulatory sequences of the NLGN4X gene were analyzed by polymerase chain reaction and direct sequencing. RESULTS: We identified a de novo 1 base pair (-335G>A) substitution located in the promoter region in a patient with autism and nonsyndromic profound MR. Interestingly, this variation is associated with an increased level of the NLGN4X transcript in the patient compared with male control subjects as well as his father. Further in vitro luciferase reporter and electrophoretic mobility shift assays confirmed, respectively, that this mutation increases gene expression and is probably caused by altered binding of transcription factors in the mutated promoter sequence. CONCLUSIONS: This result brings further insight about the phenotypic spectrum of NLGN4X mutations and suggests that the analysis of the expression level of NLGN4X might detect new cases.

Haploinsufficiency of the GPD2 gene in a patient with nonsyndromic mental retardation.

We have investigated the chromosome abnormalities in a female patient exhibiting mild nonsyndromic mental retardation. The patient carries a de novo balanced reciprocal translocation 46,XX,t(2;7)(q24.1;q36.1). Physical mapping of the breakpoints by fluorescent in situ hybridization experiments revealed the disruption of the GPD2 gene at the 2q24.1 region. This gene encodes the mitochondrial glycerophosphate dehydrogenase (mGPDH), which is located on the outer surface of the inner mitochondrial membrane, and catalyzes the unidirectional conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate with concomitant reduction of the enzyme-bound FAD. Molecular and functional studies showed approximately a twofold decrease of GPD2 transcript level as well as decreased activity of the coded mGPDH protein in lymphoblastoid cell lines of the patient compared to controls. Bioinformatics analysis allowed us to confirm the existence of a novel transcript of the GPD2 gene, designated GPD2c, which is directly disrupted by the 2q breakpoint. To validate GPD2 as a new candidate gene for mental retardation, we performed mutation screening of the GPD2 gene in 100 mentally retarded patients; however, no mutations have been identified. Nevertheless, our results propose that a functional defect of the mGPDH protein could be associated with mental retardation, suggesting that GPD2 gene could be involved in mental retardation in some cases.

De novo balanced translocation t (7;16) (p22.1; p11.2) associated with autistic disorder.

The high incidence of de novo chromosomal aberrations in a population of persons with autism suggests a causal relationship between certain chromosomal aberrations and the occurrence of isolated idiopathic autism. We report on the clinical and cytogenetic findings in a male patient with autism, no physical abnormalities and a de novo balanced (7;16)(p22.1;p16.2) translocation. G-banded chromosomes and fluorescent in situ hybridization (FISH) were used to examine the patient's karyotype as well as his parents'. FISH with specific RP11-BAC clones mapping near 7p22.1 and 16p11.2 was used to refine the location of the breakpoints. This is, in the best of our knowledge, the first report of an individual with autism and this specific chromosomal aberration.

The creatine transporter gene paralogous at 16p11.2 is expressed in human brain.

Autism is a complex neurodevelopmental disorder characterized by impairment of social interaction, language, communication, and stereotyped, repetitive behavior. Genetic predisposition to autism has been demonstrated in families and twin studies. About 5-10% of autism cases are associated with chromosomal abnormalities or monogenic disorders. The identification of genes involved in the origin of autism is expected to increase our understanding of the pathogenesis. We report on the clinical, cytogenetic, and molecular findings in a boy with autism carrying a de novo translocation t(7;16)(p22.1;p11.2). The chromosome 16 breakpoint disrupts the paralogous SLC6A8 gene also called SLC6A10 or CT2. Predicted translation of exons and RT-PCR analysis reveal specific expression of the creatine transporter paralogous in testis and brain. Several studies reported on the role of X-linked creatine transporter mutations in individuals with mental retardation, with or without autism. The existence of disruption in SLC6A8 paralogous gene associated with idiopathic autism suggests that this gene may be involved in the autistic phenotype in our patient.

Autism: an overview of genetic aetiology.

Autism is a pervasive developmental disorder characterised by impairment in social interaction and in communication, with unusual behaviour. Genetic factors are predominant in autism pathogenesis. Interactions between multiple genes cause "idiopathic" autism but epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The genetic polymorphism and the phenotypic heterogeneity make the autism a complex disorder to study. Genetic research on families with multiple affected children and biochemical mechanisms studies represent the sources for identifying the susceptibility genes in autism. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation.