MS Gene: The Eternal Attraction Of The Grail

2. November 2016

For more than twenty years the search was unsuccessful. Only now have Canadian researchers once again come across genes which increase the risk of MS significantly. A certain gene mutation resulted with 70% of its carriers in MS. However, further factors have to be added.

Is this the huge breakthrough? This hopeful question was recently asked among many neurologists. This is because several reports appeared stating that a mutation of the DNA was found which results in a 70 percent probability of multiple sclerosis. Some even spoke of having identified the MS gene.

This new information encourages researchers and those affected. This is because neurologists involved in the study of MS and its causes find themselves in a similar situation to someone literally looking for the needle in a haystack. The chances therein of finding the needle are probably greater than that of deciphering the causes of this multifactorial disease. As diverse as the causes of the disease are, so too are the manifestations of the forms of MS.

One single amino acid is to blame

A relapsing of symptoms can occur, as can a creeping irreversible destruction of nerve functions. The genetic predisposition which favours the emergence of the disease is, just as are the various conducive environmental factors, the subject of numerous studies around the world. The MS gene has however not been found as yet, even though a few locations in the DNA strands which may favour the development of the disease are already known. The likelihood of MS being raised to 70% through the mutation of a single amino acid, as published in a recent study, has until now not as yet been described.

Canadian scientists at the University of British Columbia under the direction of Dr. Carles Vilarino-Guell believe they have found mutations in the gene NR1H3, which are more strongly associated with the development of MS than are mutations in other genes. NR1H3 encodes for the liver X receptor alpha (LXRA). Subsequent to the activation of the receptor, specific factors are activated which, on the one hand regulate the metabolism of cholesterol and on the other hand have other immunosuppressive properties.

A genetic short circuit

Cholesterol has in being a membrane component an important role in the stability of the cell surface and is involved in neurotransmitter release in the CNS. In addition, cholesterol is essential for the myelination process. If the NR1H3 mutation is present, this leads, according to the recent study, to no more functional LXRa being formed and subsequent intracellular signal transduction no longer taking place. The genetic short circuit hence leads to the termination of cholesterol synthesis and, in association with this, to disorder in the myelin layer structure and disruptions in neurotransmitter flow.

Five cases of MS in one family

All of this in its entirety is conducive to the emergence of MS. While combing through a MS database the Canadian research group discovered a rare case wherein an accumulation of cases of MS appeared in the one family. This involved the primary progressive form of the neurodegenerative disease (PPMS), which is found in approximately 10-15% of MS patients. Genetic analysis of those affected and healthy family members revealed that some relatives carry the same mutation in the NR1H3 gene. Subsequent database analyses identified this genetic alteration in another family with multiple affected individuals.

Even though not all carriers of the genetic variant suffer from MS (but rather 70% as aforementioned), the authors refer to a common inheritance of the mutation and the occurrence of MS. With regard to another mutation in the same gene, the Canadian scientists here too determined a significant association between the occurrence of the gene variant and development of a case of PPMS. Cases of PPMS however occur rarely. The authors themselves estimate that one in 1,000 MS patients exhibit the pathogenesis due to the mutation. Therefore, one cannot speak in either case of the MS gene having been found.

Everything just statistics

However, other researchers became aware of the interesting results. Unfortunately, thus far these have not been able to be reproduced in independent studies. A major criticism of the published work is the very small number of patients who were used for the study. The genes of 2,053 MS patients and 799 healthy individuals have been analysed with respect to the NR1H3 mutation. Studies using larger cohorts of more than 30,000 people in the patient and control group derived from the same database, the Exome Aggregation Consortium (EXAC), show no significant association of the mutation described and the development of MS.

In addition, serious deficiencies in the statistical analysis of the collected data were noted. One important statistical parameter is, for example, the probability that the mutation and the occurrence of MS disease are inherited in coupled fashion – the so-called LOD (logarithm of odds). Usually a LOD of >3 is accepted as significant. However, the data presented only reach a value of 2.2

Too bad – say critics

The authors of the publication had to quite justifiably take some criticism. The identified deficiencies allow strong doubts to be cast on the results of the high-ranking published findings. Quite a shame, say critics such as US geneticist Dr. Chris Cotsapas: “Such a discovery would have huge implications for the diagnosis of various forms of MS, for prognosis and genetic counselling and possibly also for checking to find inconspicuous disease carriers”.

The identification of the responsible genetic hotspots are a promising approach in clarifying the principal pathomechanisms of MS and, based on that, generating new approaches. Were such a significant genetic predisposition known, one could possibly already engage therapy not only during but before the first sub-acute episodes of neurological dysfunction.

According to one recent study it’s exactly this, early intervention, which is important and conducive to an optimal therapeutic response. But we should act with caution and not be tempted into quick fixes. A similar warning comes from Dr. Daniel McArthur of the Harvard Medical School. “We must adhere to scientific principles before we draw momentous conclusions from our research data. This includes precise statistical analysis and independent replications”. It needs to be very carefully, thoroughly and cleanly further researched, so as to prevent the genetic short circuit again being followed by a scientific knee-jerk reaction.

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