While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.
The microphthalmia-associated transcription factor (MITF) locus has been mapped to human chromosome 3p12-p14.1, and encodes a basic helix-loop-helix zipper (bHLH-ZIP) protein homologous to a number of transcription factors. Numerous mutations at the mouse microphthalmia (mi) locus have been described, and all have reduced or absent pigmentation of the eyes, ears, and/or pelage, with some genotypes exhibiting small or absent eyes and osteopetrosis. The mivit/vit mutation at the mouse mi locus produces a postnatal depigmentation that resembles human vitiligo. The mice homozygous for this mi allele show a progressive loss of cutaneous, hair and ocular pigmentation with age. Vitiligo, an acquired depigmentary disorder, is characterized by patchy depigmentation of skin that generally begins around puberty and tends to become more progressive over time. There is suggestive evidence that human vitiligo may be inherited; however, the mode of inheritance is still debated and the pathogenesis is not clearly delineated. The human disorder osteopetrosis is characterized by a generalized net accumulation of skeletal mass and results from reduced osteoclast function in the bone. This is an inherited disorder and has been associated with mi in a mutant mouse. Therefore, the possible involvement of the MITF locus in the pathogenesis of either familial vitiligo or osteopetrosis was investigated. Linkage analysis was performed using microsatellite polymorphic markers D3S2465, D3S1261, and D3S1766 on genomic DNA from 26 families with vitiligo/osteopetrosis. D3S1261 is physically located at or near the MITF locus, while D3S2465 and D3S1766 are flanking the locus at about 17.5 cM genetic distance each side. Evidence from LOD score analysis surprisingly indicated that none of the families with vitiligo or osteopetrosis are linked to these short tandem repeat polymorphisms (STRPs). Thus, the human homolog (MITF) of the mouse mi gene, a good candidate gene at the phenotypic level, may not be involved in the pathogenesis of familial human vitiligo or osteopetrosis.
Abstract. In this position paper, we describe the current status and plans for a Swiss National Research Infrastructure. Swiss academic and research institutions are very autonomous. While being loosely coupled, they do not rely on any centralized management entities. A coordinated national research infrastructure can only be established by federating the local resources of the individual institutions. We discuss current efforts and business models for a federated infrastructure.
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