Press release

SINGLE GENE DEFECTS CAN MANIFEST THEMSELVES AS DISTINCT AND DIFFERENT SYNDROMES AND DISEASES IN HUMANS

As a result of several research presentations given at the Lowe Syndrome Trust UK Symposium at the Royal Society, Carlton House Terrace, London SW1 on Thursday 2^nd December, 2004, it has now become apparent that several clinical syndromes and diseases that have been reported as distinct and separate clinical manifestations in the medical literature can now, interestingly, be accounted for by mutations in one gene. Presentations from Professor Robert Nussbaum (National Human Genome Research Institute, NIH) and other researchers working on the molecular mechanisms leading to Lowe Syndrome have shown that a mutation in the OCRL-1 gene is the common cause of Lowe Syndrome which affects only young male children and presents as a wide range of clinical manifestations which clearly define the Lowe Syndrome. However, in another presentation from Professor Steve Scheiman from Upstate Medical University, New York, USA, there was data presented showing that a proportion of his patients that had been diagnosed with the phenotype of Dent’s Disease did not present with the expected gene defect in the renal chloride ion transporter (i.e. the CLCN5 gene) but rather were genetically mapped as to having mutations in the OCRL-1 gene, which is purported to be the cause of Lowe Syndrome. These studies indicate that the clinical, physiological manifestations of an OCRL-1 mutation do not singularly account for just the clinical manifestations used to describe Lowe Syndrome; rather they can be presented as another phenotype describing a different disease (Dent’s Disease) which has similar renal problems but very distinct clinical characteristics. Thus, the previously held assumption that different syndromes and diseases could be tracked through different gene mutations is now put into question, and indicate that the medical descriptions for syndromes of diseases still stand as a clinical diagnosis but they are not simply explained by a genetic mutation.

The Symposium held at the Royal Society, London was attended by 50 scientists from the UK, Europe and the USA, involved presentations from international and national researchers who had been investigating the clinical, cellular and molecular mechanisms that lead to the onset of Lowe Syndrome in young males from all societies and countries worldwide. Lowe Syndrome is caused by lack of an enzyme that affects the brain, causing seizures, epilepsy, mental retardation, speech and developmental delay, the kidneys, causing salt wasting and renal failure; the eyes, all children are born with congenital cataracts and as a result are either blind or partially sighted; and the skeleton often manifests rickets, arthritis and spinal deformities. Sadly, most Lowe children do not survive until adulthood because of these complications.

The featured Guest Speaker at this conference was Professor Robert Nussbaum, who is the Head of the Genetic Diseases Research Branch of the National Human Genome Research Institute at the NIH in the USA. Professor Nussbaum was responsible for mapping the Lowe Syndrome gene to the X-chromosome and has been a leading figure in Lowe Syndrome research, based at the National Institute of Health, Bethesda, Maryland, USA. Professor Robert Nussbaum presented an overview of the molecular cell biology and clinical manifestations of Lowe Syndrome, which was believed to be a one-gene defect in the (OCRL-1) causing this disease in humans. However, a very interesting presentation from a Professor Steve Scheiman from Upstate Medical University, New York, USA, demonstrated that the OCRL-1 mutation in patients also occurred in a sub-population of patients diagnosed with Dent’s Disease, which is another independently described syndrome presenting with renal function abnormalities. The outcome of the results and discussion of these two presentations and supporting presentations from several UK researchers, clearly indicated that clinical syndromes as they are described in the medical literature are not simply accounted by a single or multiple gene defects. The fact that both patients clinically diagnosed with Lowe Syndrome and Dent’s Disease (one of the Falconi syndromes) indicates that a common gene defect (i.e. OCRL-1 mutation) can be the cause of the disease; however, the clinical manifestations of this disease are presented as very different phenotypes in the patients, which present as a broad range of clinical manifestations in different tissues of the body.