Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mecha nobullous disorder that results from loss-of-function mutations in the genes e ncoding the basement membrane component, laminin 5. Typical...Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mecha nobullous disorder that results from loss-of-function mutations in the genes e ncoding the basement membrane component, laminin 5. Typically, there are framesh ift, splice site or nonsense mutations on both alleles of either theLAMA3,LAMB3o rLAMC2genes,withaffectedindividuals inheriting one mutated allele from each pare nt. In this report, we describe a patient with Herlitz JEB in whom DNA analysis revealed homozygosity for the recurrent nonsense mutation R635X in LAMB3, locate d on chromosome 1q32.2. However, screening of parental DNA showed that although the patient’s father was a heterozygous carrier of this mutation, the mother’s DNA showed only wild-type sequence. Subsequent genotype analysis using 13 micr osatellite markers spanning chromosome 1 revealed that the affected child was ho mozygous for the entire seriesofmarkerstestedandthatalloftheallelesoriginatedfro m the father. These results indicate that the Herlitz JEB phenotype in this pati ent is due to complete paternal isodisomy of chromosome 1 and reduction to homoz ygosity of the mutant LAMB3 gene locus. This is the fourth case of uniparental d isomy to be described in Herlitz JEB, but it represents the first example of com plete paternal isodisomy for chromosome 1 with a pathogenic mutation in the LAMB 3 gene. These findings have important implications for mutation screening in JEB and for genetic counselling.展开更多
文摘Herlitz junctional epidermolysis bullosa (JEB) is an autosomal recessive mecha nobullous disorder that results from loss-of-function mutations in the genes e ncoding the basement membrane component, laminin 5. Typically, there are framesh ift, splice site or nonsense mutations on both alleles of either theLAMA3,LAMB3o rLAMC2genes,withaffectedindividuals inheriting one mutated allele from each pare nt. In this report, we describe a patient with Herlitz JEB in whom DNA analysis revealed homozygosity for the recurrent nonsense mutation R635X in LAMB3, locate d on chromosome 1q32.2. However, screening of parental DNA showed that although the patient’s father was a heterozygous carrier of this mutation, the mother’s DNA showed only wild-type sequence. Subsequent genotype analysis using 13 micr osatellite markers spanning chromosome 1 revealed that the affected child was ho mozygous for the entire seriesofmarkerstestedandthatalloftheallelesoriginatedfro m the father. These results indicate that the Herlitz JEB phenotype in this pati ent is due to complete paternal isodisomy of chromosome 1 and reduction to homoz ygosity of the mutant LAMB3 gene locus. This is the fourth case of uniparental d isomy to be described in Herlitz JEB, but it represents the first example of com plete paternal isodisomy for chromosome 1 with a pathogenic mutation in the LAMB 3 gene. These findings have important implications for mutation screening in JEB and for genetic counselling.
