A striking discovery in medical genetics is that some apparently disparate diseases may have similar underlying genetic dysfunctions.

Take for example, familial dysautonomia (FD), described in Slaugenhaupt et al. (2001):

The loss of neuronal function in FD has many repercussions, with patients displaying gastrointestinal dysfunction, abnormal respiratory responses to hypoxic and hypercarbic states, scoliosis, gastroesophageal reflux, vomiting crises, lack of overflow tears, inappropriate sweating, and postural hypotension.

In that paper Slaugenhaupt et al. described mutations in a gene called Elp3. The ELP3 protein is one of six components that make up the Elongator complex. In molecular biology, a complex just means a collection of several proteins, which is not an unusual because proteins often work together. Elongator is necessary for modifying a very small protein called alpha-tubulin. Alpha-tubulin is itself what makes up microtubules, a major part of the cells cytoskeleton. You can think of the cytoskeleton as doing the same thing for a cell as out skeleton does for us: primarily offering structural support. But at the molecular level the cytoskeleton also acts as the tracks for moving other molecules around the cell, they can direct the transport of specific proteins to appropriate areas of the cells. This important function is mediated by things like Elongator, which modify the mircotubules providing signals to protein packages which will use them to move around the cell. This is all referred to as intracellular trafficking, which sounds much more seedy than it actually is. When the transportation mechanism of the cells become compromised, unpredictable consequences can ensue, such as FD.

It’s like if signals in a rail network get damaged. Trains may still reach their destination, but perhaps they are late. Cargo will arrive, but not as much as expected, or perhaps in the wrong location, and there can be a backlog of people milling about with nothing to do. Several different consequences can occur.

An interesting correlation is that the same problem of microtubule modification occurs in neurons of people suffering from Huntington’s disease. The causative gene of Huntington’s, htt, has recently been implicated in intracellular trafficking. Not exactly like with Elongator, but in the same cellular process. Elongator, however, is implicated in other neurological disorder: Amyotrophic lateral sclerosis (ALS) and rolandic epilepsy. That these seemingly disparate neurological conditions may have similar underlying molecular underpinnings presents an exciting inroad into understanding their origins and possible treatments.

Image: Ratbum via Flickr
Citation:

Nguyen, L., Humbert, S., Saudou, F., & Chariot, A. (2010). Elongator – an emerging role in neurological disorders Trends in Molecular Medicine, 16 (1), 1-6 DOI: 10.1016/j.molmed.2009.11.002

Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, & Gusella JF (2001). Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. American journal of human genetics, 68 (3), 598-605 PMID: 11179008