PMC:1584416 / 29568-32355 JSONTXT

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In contrast to two hemizygous XPDXPCS patients carrying the XPDG47R- or XPDR666W-encoding alleles who died of the disease before 2 y of age, two compound heterozygous XPDXPCS patients carrying the same XPDG47R- or XPDR666W-encoding alleles in addition to the presumed null XPDL461V+del716−730 both had considerably milder disease symptoms and survived more than ten times longer (A. Lehmann, personal communication) (Figure 5). Compound heterozygosity is also associated with the recently reported combination XP and TTD (XPTTD) syndrome [8]. Similar to the XpdTTD/†XPCS and XpdTTD/†XP mice described here, both patients with XPTTD described so far had intermediate hair cysteine values. Furthermore, XPTTD patient XP38BR carried a “causative” TTD mutation in one allele and a novel point mutation encoding XPDL485P in the other. Although the XPDL485P-encoding allele fails to complement viability in the haploid S. pombe rad15 deletion strain and is thus interpretable as a null allele [8], we nonetheless suggest that the combined XPTTD phenotype in this patient involves phenotypic contributions from both alleles. Taken together, these data suggest a shift to a biallelic paradigm for compound heterozygous patients in XP complementation group D.\nFigure 5 Genotype–Phenotype Relationships in XPD Disorders\nAccording to the current monoallelic hypothesis, phenotype is determined solely by the causative allele product. If a second, different allele is present, it is considered a functional null. There is a lack of any correlation between the site of the XPD mutation and the resulting disorder. We propose a biallelic hypothesis for compound heterozygotes in which both alleles can contribute to the phenotype. Examples of compound heterozygous patients in which a second, presumed null allele is likely to contribute to disease outcome are provided above in comparison to corresponding homo- or hemizygous patients with the same causative allele. Numbers in the schematic of the protein indicate the helicase 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