When Two Mutants Collide: How Genetic Disorders Can Be Partially Rescued In Compound Heterozygotes

In recessive disorders, such as the three clinically distinct disorders trichothiodystrophy (TTD), xeroderma pigmentosum (XP), and Cockayne syndrome (CS), all of which involve different mutant alleles in the XPD gene, two copies of the individual mutant allele are needed for disease manifestation. However, understanding how these different mutant alleles interact with one another is difficult in humans due to our inability to distinguish environmental and background effects from genetic effects.

In a new study published online in the open access journal PLoS Biology, Jaan-Olle Andressoo, James Mitchell, and colleagues investigate interactions between mutant XPD alleles using compound heterozygote mice that have the recessive mutant TTD allele on one chromosome, and a different mutant allele on the other. They linked physical traits to different combinations of mutant alleles and found that combinations of these alleles were able to alleviate disease symptoms and improve the function of the interacting genes.

Each of these disorders has distinct manifestations and associated risks, and in mice, some of the same physical traits are apparent. An existing "monoallelic" paradigm states that mutations either cause a specific XPD syndrome, or they don't, in which case they are considered "null." However, as some patients presented with rare combinations of TTD and XP symptoms in apparently "biallelic effects," this revealed the limitations of this paradigm. The authors investigated the potential for these "biallelic" effects in mice by creating compound heterozygote mice that combined an existing TTD causing mouse model, a homozygous lethal CS mutant identified in a hemizygote patient, and another homozygous lethal XP causing allele. Combining a copy of one of these homozygous lethal alleles with a recessive TTD allele demonstrated a reduction in severity of multiple skin, hair, and aging-related features of TTD in the compound heterozygotes.

Additionally, alleviation of anemia and developmental delay symptoms were seen, and lifespan was extended. The XP lethal allele in combination attenuated the TTD-related skin and weight loss symptoms. This combination of alleles also allowed the normally sun-sensitive CS and XP cells to better survive ultraviolet light, which implies some kind of "interallelic complementation" is occurring (when the two alleles interact and produce an effect that neither has on its own).

Therefore, some presumed "null" alleles may still influence disease outcome in compound heterozygous patients as seen here in mice. It seems that a biallelic paradigm should be adopted for compound heterozygous patients with XPD-related disorders.