Identification of 31 genomic loci for autosomal recessive mental retardation and molecular genetic characterization of novel causative mutations in four genes.

Severe mental and behavioral disorders are common, affecting 1-3% of the world populace. They thus constitute a major burden not only for the affected families but also for society. There is reason to believe that autosomal recessive mental retardation (ARMR) is more common than X-linked MR, but it has so far received considerably less attention. This is partly due to small family sizes and low consanguinity rates in industrialized societies, both of which have hampered gene mapping and identification, which is illustrated by the fact that until 2003, when this study was started, no more than one gene was shown to be implicated in non-syndromic ARMR (NS-ARMR). The work presented here is part of a larger project to shed more light on the molecular causes of ARMR as a prerequisite for diagnosis, counselling and therapy, focusing on large consanguineous Iranian families with several mentally retarded children. It combines clinical and molecular approaches such as patient recruitment, clinical characterization, sample collection, SNP array genotyping, whole genome linkage analysis, homozygosity mapping and finally mutation screening in a systematic fashion. Successful mutation detection is followed by functional analyses of the affected genes. In the study presented here, the investigation of 135 families led to the identification of 31 novel genomic loci for ARMR. Contrary to previous observations, which prima facie argued against the existence of frequently mutated genes, overlapping autozygosity regions from several families could now be observed on chromosomes 1, 5 and 19. At each of these loci a minimum of two overlapping linkage intervals were solitary in the respective families and showed a LOD score of, or above, three. Mutation screening in one of these families with NS-ARMR has led to the discovery of a new gene for NS-ARMR, TUSC3, where a mutation was found that leads to the loss of TUSC3 transcript in patient cells. Additional investigations in families with syndromic forms of ARMR revealed a new gene for ataxia and mild mental retardation. This gene, CA8, was found to carry a R237Q mutation, with a putatively deleterious effect on functional properties of the gene product in the affected patients. Furthermore one novel mutation in ALDH3A2 in patients with Sjögren-Larsson syndrome and two in the MCPH1 gene in patients with primary microcephaly were found. Gene expression profiling, knockdown experiments and irradiation studies added more evidence on the involvement of MCPH1 in cell cycle control, DNA damage response and transcriptional regulation. In summary, the identification of a novel gene for NS-ARMR and many new genomic intervals with a high probability for containing different genes with disease causing mutations is in keeping with previous results that indicated a high degree of genetic heterogeneity for this disorder. Still, the several overlapping loci found in this study now also indicate the presence of genes with an increased frequency of mutations in ARMR patients. Further studies are necessary to identify the disease causing mutations in these newly identified linkage intervals and to determine the contribution of the affected genes to the complex processes of human cognition. These studies will be greatly facilitated by the novel high throughput sequencing technologies, which are now available and that will allow a much increased pace for the detection of disease causing mutations