Xinhua Shu

Lifespan and mitochondrial control of neurodegeneration

We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steady-state RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.

Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2

BACKGROUNDnElevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2).nnnMETHODSnTwo unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations.nnnRESULTSnTwo novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions.nnnCONCLUSIONSnThis is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.

Biochemical Characterisation of the C1QTNF5 Gene Associated with Late-Onset Retinal Degeneration

Age-related macular degeneration (AMD) is the commonest cause of severe vision loss in adults, affecting up to 30% of the elderly population and accounting for 50–60% of new blind registration in western countries (Green and Enger, 1993; Seddon, 2001). It is characterised by a late-onset degeneration of the retinal macula and represents the advanced stage of a more common disorder, age-related maculopathy. There are two clinical subtypes of AMD, one is a “dry” form characterised by geographic atrophy, the other a “wet” form characterised by choroidal neovascularisation (CNV). This “wet” form represents only 10% of cases but accounts for about 90% of registered blindness (Ferris et al., 1984). The important early pathological features of AMD are the presence of both focal (drusen) and diffuse extracellular (basal) deposits in the macula, between the retinal pigment epithelium (RPE) and inner collagenous layer of Bruch’s membrane, a pentalaminar structure bounded by the basement membranes of RPE and choroidal capillary 1endothelium. These deposits lead to dysfunction and later death of RPE and associated photoreceptors. The nature of the proteins within the diffuse extracellular deposits have not been elucidated but the focal deposits (drusen) include >100 proteins, together with esterified and non-esterified cholesterol and other lipids and glycosaminoglycans (Crabb et al., 2002; Malek et al., 2003). Risk factors for AMD include age, sex, family history, APOE genotype, smoking, ethnicity and cardiovascular disease (Seddon, 2001). Genetic factors are implicated in AMD on the basis of twin and family studies but it appears to be a genetically complex disorder (Hammond et al., 2002).

X-Linked Retinal Dystrophies and Microtubular Functions Within the Retina

RP is one of the most heterogeneous genetic disorders known in man (1). There are currently about 40 genes known or identified in this group of disorders (2). Most cases result from one of a series of monogenic disorders inherited in an autosomal, X-linked or mitochondrial manner. The extent to which it includes a subset of oligogenic or even polygenic conditions is unclear. Oligogenic inheritance has been established in a small proportion of RP families, for example, a combination of mutations in the ROM1 and RDS/peripherin (PRPH2) genes (3). A significant excess of RP simplex cases (singleaffected individual within a family) has been reported in segregation analyses, suggesting that 12 to 40% of all RP results from nongenetic causes, new mutations, or complex inheritance (4,5). The early literature also found a significant excess of affected males relative to females (6,7) (e.g., Nettleship [6] found a ratio of 1.6:1) and that males were less likely than females to transmit the disease to their offspring (7)— both suggesting the possibility of X-linkage. This question needs to be revisited in the light of recent molecular findings, as discussed in the section on the RPGR gene.