The Pathobiology of "Autosomal Dominant"

Have you ever wondered why certain traits are autosomal dominant and others are autosomal recessive?

In most cases, the explanation is fairly straightforward. Diseases, such as Huntington's or myotonic dustrophy, which are transmitted in an autosomal dominant fashion are mostly due to the toxic effect of the mutant protein encoded by the abnormal gene. This protein builds up inside the endoplasmic reticulum and interferes with the synthesis of other vital proteins, which then leads to the abnormal phenotype.

With autosomal recessive inheritance, it is usually an useful function that is lost. Both alleles encoding an essential protein are lost, and thus the product can no longer be synthesised, for e.g. the CFTR protein in cystic fibrosis.

There are notable exceptions to this general principle. Sometimes, the product of one normal allele is insufficient to perform the requisite function of the putative gene. This is called haploinsufficiency. Thus, the condition is transmitted as autosomal dominant, with a dose-response gradient between those heterozygous and homozygous for the abnormal allele. Examples of haploinsufficiency contributing to autosomal dominant transmission are dyskeratosis congenita, Williams syndrome and autosomal dominant retinitis pigmentosa. Marfans and Ehlers Danlos syndromes are also inherited in a similar way.

A different, but nonetheless fascinating mechanism of autosomal dominant inheritance is illustrated by an autoinflammatory condition called TRAPS (TNF Receptor Associated Periodic Syndrome). In this syndrome, the 55 kDa TNF receptor on the cell surface is abnormal, and does not shed on binding to the pro-inflammatory cytokine TNF alpha. Thus prolonged signalling through TNF alpha leads to an augmented inflammatory response, with excessive production of NF-kappa B. Further, it is thought that the usual neutralising effect of circulating "soluble" (non-membrane bound) TNF receptor on TNF alpha is reduced.

The TNF alpha receptor is homotrimeric, i.e. it is composed of three similar units. Most subjects with TRAPS have only 1 abnormal allele, usually due to a missense mutation, while the other allele is normal. However, assuming that even one mutated component of the trimer would lead to abnormal receptor function, one can see that even with one normal allele, 7 out of 8 receptors would be abnormal (the odds are only 1 in 2^3 that in a given trimeric receptor, all 3 components would be from the normal allele). Thus, the condition would transmit as autosomal dominant.