Autism

Grouphead: PD Dr. Sabine M. Klauck
Members: Dr. Geeta Pakalapati, Dr. Bärbel Felder, Andreas Chiocchetti, Kinga Przibilla, Tatjana Salvi
Former members: Dr. Kim Beyer, Dr. Stefanie Rauskolb

Autism is a severe developmental disorder characterized by marked social deficits, deviant language and a restricted range of stereotyped repetitive behaviours usually occurring within the first three years of life (Klauck, 2006). The prevalence for autistic disorder representing the narrow phenotype is at least 5/10,000 births and the ratio of affected male to female is 4:1. A genetic etiology of autism is strongly supported by family and twin studies. There may be at least three to four genes involved interacting together with a complex mode of inheritance, but also up to 100 genes have been discussed.

The goal of our project is to identify disease genes for autism with two main approaches. Firstly, a genome wide linkage study using the affected sib-pair method was performed in collaboration with the "International Molecular Genetic Study of Autism Consortium” (IMGSAC). Secondly, family-based association studies of the division’s patient sample examined polymorphic markers in candidate genes and defined gene loci. In addition several candidate genes from the regions identified in the genome wide linkage studies were screened systematically for functional variants in autistic probands.

In the first approach a two-stage genome screen initially identified regions on six chromosomes in a sample of 99 sib-pair families (IMGSAC, 1998), showing the most significant result on chromosome 7q31-q35 with a multipoint maximum lod score (MLS) of 3.55. A follow-up study using an extended sample of 153 sib-pairs generated a MLS of 3.37 at D7S477 in 7q22 in addition to further candidate regions on chromosomes 2q, 16p and 17q (IMGSAC, 2001a). Linkage disequilibrium mapping identified two regions of association – one lying under the peak of linkage, the other some 27 cM distal. These results are supported in part by findings in our singleton sample and an independent American singleton sample (IMGSAC, 2001b, Beyer, K. 2001 PhD thesis). A fine mapping approach was carried out resulting in an integrated 3 Mb BAC and transcript map in 7q31-q32, which should help to identify susceptibility genes for infantile autism (Beyer, K. 2001 PhD thesis, Beyer et al., 2001). Sex and parent of origin linkage modelling using an expanded sample of 219 affected sib-pairs suggested possible sex-limited effects of susceptibility loci on 7q, 15q and 16p, and parent-of-origin effects on 7q and 9p (Lamb et al., 2005).

The second approach included the analysis of candidate genes using family-based association studies and/or mutational analyses. The genes WNT2 (Beyer, K. 2001 PhD thesis), RELN (Beyer, K. 2001 PhD thesis, Bonora et al., 2003); FOXP2 (Newbury et al., 2002), PEG/MEST, COPG2, CPA1 and CPA5 (Bonora et al., 2002), CUTL1, SRPK2, SYPL, LAMB1, NRCAM and PTPRZ1 (Bonora et al., 2005) - all located within the candidate region on chromosome 7q - were tested; however, all variants analysed were shown not to be of major relevance towards the autistic phenotype in the patient sample under study. Likewise, further candidate genes from other genomic regions [HOPA, Xq13, (Beyer, K. 2001 PhD thesis, Beyer et al., 2002a); MECP2, Xq28, (Beyer, K. 2001 PhD thesis, Beyer et al., 2002b)] could be ruled out as main factors for the etiology of infantile autism.

We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism (Klauck et al., 2006), a multicenter study with colleagues of the Universities of Frankfurt (F. Poustka) and Salzburg (L. Breitenbach-Koller). Based on the findings that the amino-acid substitutions confer hypomorphism with respect to the regulation of the translation process and high expression of RPL10 in hippocampus, we suggest a novel modulating disease mechanism for autism. A change in translational function may impact on those cognitive functions that are mediated through the limbic system.

Recently, the largest genome screen ever in autism research conducted by the Autism Genome Project (AGP) Consortium with participation of our group revealed a new susceptibility locus on chromosome 11p12-p13 and the gene neurexin 1 (NRXN1) to be involved in autism. In total 1,168 families with at least two affected individuals have been analyzed using Affymetrix 10K SNP arrays for linkage and copy number variations in families. Interestingly, genetic components of the synaptic glutamatergic signaling system including neurexin seem to be promising candidates for contributing to autism spectrum disorders (The Autism Genome Project Consortium, 2007).

In collaboration with: F. Poustka (Department of Child and Adolescent Psychiatry, J. W. Goethe Universität Frankfurt); The International Molecular Genetic Study of Autism Consortium (IMGSAC); L. Breitenbach-Koller  (Department of Cell Biology, Paris-Lodron University Salzburg);  A. Benner (Biostatistics, DKFZ)