Systematic analysis of the chromosomal region Xq28

Annemarie Poustka †

Former members: Petra Kioschis, Bernhard Korn, Nina Heiss, Ute Rogner, Inge Krebs, Anja Kolb

We selected the human chromosomal region Xq28 to develop genomic technologies that should be applied to map genomic clones and to identify and clone all genes. The analysis of this subchromosomal region has hence served as a model system for analysis of the whole human genome. The importance of this region arises from the high gene density and the large number of genetic disorders linked to this 10 Mb region.

The systematic generation of physical and transcription maps allowed the identification of most genes localized in this region, and was key in the hunt for new disease genes. Our work substantially contributed to make Xq28 one of the best characterized regions of the human genome (Aradhya 2002, McPherson 2001, Nadeau 2001). Consequently, the division was deeply involved also in the international initiative that pursued the complete sequence analysis of chromosome X (Ross 2005).

Based on the establishment of genetic maps of the subchromosomal region Xq28, several candidate genes for genetic disorders were isolated: MTM1 causes X-linked myotubular myopathy (Laporte 1996); the DKC1 gene causes the X-linked recessive disease 'dyskeratosis congenita' (Heiss 2000); a mutation in the MECP2 gene was found to be the cause of one rare form of mental retardation - PPM-X syndrome (Klauck 2002); Genomic rearrangements in the NEMO gene impairs NF-kappaB activation and is a cause of incontinentia pigmenti (Smahi 2000). Furthermore, mutations in the RPL10 gene have been identified in Autism patients (Klauck 2006), making this a new candidate for autism spectrum disorders.

In-situ hybridization images from the

Although most of these genes have been identified and sequenced, the extent of characterization at the level of expression and function varies for the genes in Xq28, making correlations between the genotype and the phenotype of genetic disorders almost impossible. Systematic functional analysis of all genes that localise to this special region has been carried out using RNA in situ hybridization and Northern blot analysis to investigate the developmental and tissue-specific expression of orthologous genes in the mouse (Kolb 2006).

This work is complemented by the systematic subcellular localization of the corresponding proteins. Since, the technologies and applications that had originally been developed in the Xq28-project have been utilized for the cloning of human genes and the systematic functional analysis of the encoded proteins. This work is carried out in the different groups and projects of the division. For example, the Xq28-region of the human genome is among the best covered with ORF-clones of the International ORFeome Collaboration, the intitial identification and characterization of the DMBT1-gene was driven by the technological developments made during the work on Xq28, and the identification of the RPL10 gene as a putative disease-gene in autism has been yet another achievement of the systematic analysis of this chromosomal region.

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