Gene Mapping And FLG Gene Mutation Analysis In Four Ichthyosis Vulgaris Families

Ichthyosis vulgaris (IV) is a common heritable skin disorder, with a prevalence estimated at 1 in 250 to 5, 300 worldwild and about 0.23% in the Chinese population. The onset of IV is usually within one year after birth. The patients manifest with dryness of skin, white scaling on the extensor surfaces of the extremities and occassionally the trunk. Clinical features also include hyperinearity of the palms and soles, atopy and heat intolerance or keratosis pilaris. Usually, ichthyosis vulgaris is inherited in autosomal dominant pattern, with genetic heterogeneity. To date, only one gene responsible for IV, the filaggrin gene (FLG), was identified. IV is an autosomal semi-dominant disease with partial penetrance owing to FLG gene mutations. Individuals homozygous or compound heterozygous were severely affected while heterozygous were only mildly or not affected.In our study, four Chinese IV families were collected. Different strategies were carried out to domonstrate the genetic basis of the disease in these four families. The whole genome wide scan and linkage analysis was performed on IV family 1, which is the-largest family with 4 generations. The maximum two-point LOD score 1.94 (calculated according to 18 members) and 2.84 (calculated according to 26 members) was obtained at marker D1S498 (at recombination fractionθ=0). Haplotype analysis localized disease locus to a 9.7cM (11.4Mb) critical region between D1S2612 and D1S2635, in which filaggrin gene is included.According to the mapping results in family 1 and known disease gene for IV, FLG was screened for mutation in these four families. 3 exons of FLG were PCR amplified and sequenced. In family 1, we found heterozygous c.3321delA mutation, heterozygous c.7945delA mutation and compound heterozygous c.3321delA/c.7945delA mutations. In family 2, we found heterozygous c.3321delA mutation and homozygous c.3321delA mutation. In family 3, we found heterozygous c.3321delA mutation. In family 4, we dectected no FLG mutation. 180 controls in China were also analyzed and two of them carried c.7945delA mutation. FLG was the causative gene for family 1, family 2 and family 3. No mutation of FLG was detected in family 4, suggesting that the mutation in non-coding sequence of FLG or other unknown gene cause ichthyosis vulgaris of family 4.