Identification of a Second HS Locus to Chromosome

A genome-wide scan was performed on DNA from 13 members of Family 13; 9 with HS and 7 unaffected. A cluster of markers on chromosome 19 co-segregated with the disease giving a highest two-point LOD score of 3.66 at recombination fraction with D19S414 (Table 2.18). Higher density markers were then taken from data on the Human Genome Browser and were run on the samples from Family 13 in order to define the limits of the candidate region. Recombination events narrowed the region to a 16.8-cM region between D19S911 and D19S1170 over the centromere of chromosome 19. The region contains 15 known genes and 6 predicted genes.

The apparent hormonal influence of HS made the oestrogen receptor-a a good candidate gene. HS symptoms usually begin post puberty and the average age of onset is early to mid-twenties. There have only been a few reports of prepubertal HS and these cases have usually been associated with precocious puberty or a hormonal imbalance [42]. Women are significantly more frequently affected by the disease then men and also often describe a premenstrual flare of the disease [25]. Symptoms tend to improve after the menopause [61]. There were however no obvious differences in hormone levels between patients and controls [2] suggesting that any hormonal influence may take place at the receptor level.

The physiological effects of oestrogen are mediated by the oestrogen receptor, a member of the nuclear receptor superfamily of transcription factors [34, 56, 62]. Oestrogen is known to exert an effect on reproductive activity but is also involved in the circulatory system, bone reabsorption and immune system. Oestrogens have significant effects on the skin and administration of oestrogen has been correlated with proliferation of basal cells in the epidermis and increased production of collagen [44, 55]. The increased oestrogen concentration affects secondary sexual characteristics in both males and females as large doses of oestrogen can increase or reduce the size of sebaceous glands and also apocrine sweat glands [44, 55]. An abnormality in the sizes of these glands has not been reported in HS but one report has demonstrated that the hair follicles in HS patients were larger than normal [28]. Oestrogen is involved in the production of pubic hair and both receptors are expressed in the hair follicle, and therefore may also exert an influence on the size of the hair follicles and contribute to the pathogenesis of HS [55]. It is therefore expressed in the appendages involved in HS and a mutation in one of these receptors could give a tissue-specific phe-notype. This may be possible due to the presence of a large number of differentially expressed 5' regions that are hypothesized to give the receptors tissue specificity.

Polymorphisms were discovered in the ER-a gene of HS patients demonstrating that both ge-nomic alleles were present. However, one or a small number of exons might be deleted and thus escape detection using an exon by exon PCR strategy. Southern analysis or long-range PCR can detect such deletions. Obtaining mRNA from affected individuals carrying heterozygous exonic polymorphisms would also reveal whether both alleles were being expressed.

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