Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene.

SOX18 mutations in humans are associated with both recessive and dominant hypotrichosis-lymphedema-telangiectasia syndrome (HLTS). We report two families with affected children carrying a SOX18 mutation: a living patient and his stillborn brother from Canada and a Belgian patient. The two living patients were diagnosed with HLTS and DNA analysis for the SOX18 gene showed that both had the identical heterozygous C > A transversion, resulting in a pre-mature truncation of the protein, lacking the transactivation domain. Both living patients developed renal failure with severe hypertension in childhood for which both underwent renal transplantation. To our best knowledge this is the first report of renal failure associated with heterozygous mutations in the SOX18 gene. We conclude that this specific mutation results in a new, autosomal dominant condition and propose the acronym HLT-renal defect syndrome for HLTRS.

The sweet thing about Type 1 diabetes: a cryoprotective evolutionary adaptation.

The reasons for the uneven worldwide distribution of Type 1 diabetes mellitus have yet to be fully explained. Epidemiological studies have shown a higher prevalence of Type 1 diabetes in northern Europe, particularly in Scandinavian countries, and Sardinia. Recent animal research has uncovered the importance of the generation of elevated levels of glucose, glycerol and other sugar derivatives as a physiological means for cold adaptation. High concentrations of these substances depress the freezing point of body fluids and prevent the formation of ice crystals in cells through supercooling, thus acting as a cryoprotectant or antifreeze for vital organs as well as in their muscle tissue. In this paper, we hypothesize that factors predisposing to elevated levels of glucose, glycerol and other sugar derivatives may have been selected for, in part, as adaptive measures in exceedingly cold climates. This cryoprotective adaptation would have protected ancestral northern Europeans from the effects of suddenly increasingly colder climates, such as those believed to have arisen around 14,000 years ago and culminating in the Younger Dryas. When life expectancy was short, factors predisposing to Type 1 diabetes provided a survival advantage. However, deleterious consequences of this condition have become significant only in more modern times, as life expectancy has increased, thus outweighing their protective value. Examples of evolutionary adaptations conferring selection advantages against human pathogens that result in deleterious effects have been previously reported as epidemic pathogenic selection (EPS). Such proposed examples include the cystic fibrosis mutations in the CFTR gene bestowing resistance to Salmonella typhi and hemochromatosis mutations conferring protection against iron-seeking intracellular pathogens. This paper is one of the first accounts of a metabolic disorder providing a selection advantage not against a pathogenic stressor alone, but rather against a climatic change. We thus believe that the concept of EPS should now include environmental factors that may be nonorganismal in nature. In so doing we propose that factors resulting in Type 1 diabetes be considered a result of environmental pathogenic selection (EnPS).

Is hemochromatosis a risk factor for Alzheimer's disease?

Excess iron accumulation in the brain is a consistent observation in Alzheimer's Disease. Iron affects amyloid precursor protein (AbetaPP) processing and promotes deposition of Abeta. Iron is also among the most potent biological toxins because of its ability to react with oxygen to form reactive oxygen species. Consequently, elucidation of the mechanisms associated with maintaining brain iron homeostasis is fundamentally important to understanding the underlying pathogenesis in AD. The iron overload disorder, Hemochromatosis, is the most common genetic disorder (1:200) so a significant percentage of AD patients can be expected to carry this mutation. Heterozygotes for this mutation also have an increased, but sub-clinical iron burden. Given the high percentage of the population who are at significant risk for iron overload, we propose that the hemochromatosis mutation be considered as a confounding factor when evaluating the contribution of genetic associations with AD and treatment strategies and efficacy. Two recent papers and new evidence presented here that the protein associated with hemochromatosis is expressed on blood vessels, choroid plexus and the ependymal cells in the brain are offered as support for this proposal.

Are hereditary hemochromatosis mutations involved in Alzheimer disease?

Mutations in the class I-like major histocompatibility complex gene called HFE are associated with hereditary hemochromatosis (HHC), a disorder of excessive iron uptake. We screened DNA samples from patients with familial Alzheimer disease (FAD) (n = 26), adults with Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52) healthy normal individuals, for two HHC point mutations-C282Y and H63D. Because the apolipoprotein E (ApoE) E4 allele is a risk factor for AD and possibly also for dementia of the AD type in DS, DNA samples were also ApoE genotyped. Chi-squared analyses were interpreted at the 0.05 level of significance without Bonferroni corrections. In the pooled healthy normal individuals, C282Y was negatively associated with ApoE E4, an effect also apparent in individuals with DS but not with FAD. Relative to older normals, ApoE E4 was overrepresented in both males and females with FAD, consistent with ApoE E4 being a risk factor for AD; HFE mutations were overrepresented in males and underrepresented in females with FAD. Strong gender effects on the distribution of HFE mutations were apparent in comparisons among ApoE E4 negative individuals in the FAD and healthy normal groups (P < 0.002). Our findings are consistent with the proposition that among ApoE E4 negative individuals HFE mutations are predisposing to FAD in males but are somewhat protective in females. Further, ApoE E4 effects in our FAD group are strongest in females lacking HFE mutations. Relative to younger normals there was a tendency for ApoE E4 and H63D to be overrepresented in males and underrepresented in females with DS. The possibility that HFE mutations are important new genetic risk factors for AD should be pursued further.