Narcolepsy-cataplexy is a disabling sleep disorder characterized by excessive daytime sleepiness and abnormal REM sleep. The development of human narcolepsy involves environmental factors acting on a specific genetic background. The importance of environmental factors is evidenced by the reported 25 to 31% of monozygotic twins who are concordant for narcolepsy. One of the predisposing genetic factors is located in the MHC DQ region. More than 85% of all narcoleptic patients with definite cataplexy share a specific HLA allele, HLA DQB1*0602 (most often in combination with HLA DR2), compared with 12 to 38% of the general population, as evaluated in various ethnic groups. Genetic factors other than HLA are also likely to be involved. Even if genuine multiplex families are rare, 1 to 2% of the first-degree relatives of narcolepsy patients manifest the disorder, compared with 0.02 to 0.18% in the general population. Studies using a canine model of narcolepsy illustrate the importance of non-MHC genes in disease predisposition. In this model, narcolepsy is transmitted as a single autosomal recessive trait, canarc-1. In spite of an association with immune-related polymorphisms, narcolepsy does not appear to be a classic autoimmune disease. Other pathophysiologic models involving the microglia and the release of specific cytokines in the CNS may be involved and are being explored. This approach, together with positional cloning studies in humans and canines, should reveal the cause of narcolepsy and open new therapeutic avenues.

Genetic and familial aspects of narcolepsy

We describe here the results of a search of Mendelian inheritance in man, GENDIAG and other sources which suggest that, in comparison with autosomes 1, 2, 3, 4 and 11, the X chromosome may contain a significantly higher number of sex- and reproduction-related (SRR) genes. A similar comparison between X-linked entries and a subset of randomly chosen entries from the remaining autosomes also indicates an excess of genes on the X chromosome with one or more mutations affecting sex determination (e.g. DAX1), sexual differentiation (e.g. androgen receptor) or reproduction (e.g. POF1). A possible reason for disproportionate occurrence of such genes on the X chromosome could be that, during evolution, the 'choice' of a particular pair of homomorphic chromosomes for specialization as sex chromosomes may be related to the number of such genes initially present in it or, since sex determination and sexual dimorphism are often gene dose-dependent processes, the number of such genes necessary to be regulated in a dose-dependent manner. Further analysis of these data shows that XAR, the region which has been added on to the short arm of the X chromosome subsequent to eutherian-marsupial divergence, has nearly as high a proportion of SRR genes as XCR, the conserved region of the X chromosome. These observations are consistent with current hypotheses on the evolution of sexually antagonistic traits on sex chromosomes and suggest that both XCR and XAR may have accumulated SRR traits relatively rapidly because of X linkage.

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An apparent excess of sex- and reproduction related genes on the human X chromosome

Comparative genomics: lessons from cats

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder in which affected individuals develop variable combinations of parathyroid, anterior pituitary, endocrine pancreatic, and duodenal tumors (Metz et al. 1994). The PYGM (muscle glycogen phosphorylase) marker at chromosome 11q13 originally was found to be linked to MEN1, showing no recombination with the MEN1 phenotype (Larsson et al. 1988; Nakamura et al. 1989; Petty et al. 1994; Kytola et al. 1995; Smith et al. 1995; Courseaux et al. 1996). However, recombinants between the MEN1 phenotype and more centromeric and telomeric markers have narrowed the MEN1 locus to a ∼2-Mb interval flanked by the markers D11S1883 and D11S449 (Courseaux et al. 1996; Debelenko et al. 1997a). The MEN1 gene is suspected to encode a classic tumor suppressor gene based on the observed loss of heterozygosity (LOH) for markers at 11q13 present in MEN 1 tumors, as well as in sporadic tumors of the types seen in familial MEN 1 (Larsson et al. 1988; Friedman et al. 1989, 1992; Debelenko et al. 1997b; Dong et al. 1997). Tumor deletion studies have suggested that the disease locus lies just telomeric to PYGM, narrowing the location of the MEN1 gene to a 600-kb region between PYGM and D11S449 (Bystrom et al. 1990; Lubensky et al. 1996; Emmert-Buck et al. 1997).

At present only two genes, ZFM1 (Toda et al. 1994) and FAU1 (Kas et al. 1993a), have been assigned to the minimal MEN1 interval, PYGM–D11S449 (Courseaux et al. 1996). Both genes have been excluded as candidates for MEN 1 based on mutation analysis (Kas et al. 1993b; Courseaux et al. 1996). Here we report the isolation, mapping, characterization, and mutation analysis of 21 transcripts contained in the 1-Mb region from PYGM to D11S4907, with the most intensive effort focusing on the genes in the PYGM to D11S449 interval. The transcript map, however, includes 33 transcripts spanning the 2.8-Mb interval between D11S480 and D11S913.

/pdf/a-transcript-map-for-the-2-8-mb-region-containing-the-1p6i51dl8y.pdf

[No Value] Vorechovsky

Papers

Report of the Fifth International Workshop on Human Chromosome 11 Mapping 1996.