of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of “null” alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

Effects of mutations in Xpd were investigated in mice. Compound heterozygotes of otherwise homozygous lethal alleles demonstrated interallelic complementation and partial phenotypic rescue of XPD-related disease symptoms.

Introduction
Interallelic complementation is defined as the ability of two differentially mutated alleles to function better together than either can on its own. Despite its near universality in lower organisms [1], its potential to contribute to clinical heterogeneity in human disease is seldom considered. Evidence of interallelic complementation at clinically relevant loci is limited to biochemical and cell-based studies of a handful of metabolic disorders with defects in enzymes including propinyl-CoA carboxylase [2], argininosuccinate lyase [3], galactose-1-phosphate uridylyltransferase [4], and methylmalonyl CoA mutase [5].
Compound heterozygotes are individuals carrying two different mutant alleles of the same gene. In the absence of a dominant (wild-type [wt])