An SCN9A channelopathy causes congenital inability to experience pain

The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.     

Genetic linkage of Werner's syndrome to five markers on chromosome 8.

Werner's syndrome (WS) is a rare autosomal recessive disease in which the affected individuals display symptoms of premature ageing. The substantial phenotypic overlap between WS and normal ageing indicates that these two conditions may have pathogenetic mechanisms in common. The WS mutation has pleiotropic effects, and patients and their cells show many differences compared with normals. Despite extensive study of the clinical and biochemical features of this disorder, the primary genetic defect remains unknown. We have undertaken a genetic linkage study in an effort to identify the locus of the primary defect. Here we report close genetic linkage of the WS mutation to a group of markers on chromosome 8.     

ASPM is a major determinant of cerebral cortical size

One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. Humans with autosomal recessive primary microcephaly (MCPH) show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation. Genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex. Here we show that the most common cause of MCPH is homozygous mutation of ASPM, the human ortholog of the Drosophila melanogaster abnormal spindle gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. The mouse gene Aspm is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis. Notably, the predicted ASPM proteins encode systematically larger numbers of repeated 'IQ' domains between flies, mice and humans, with the predominant difference between Aspm and ASPM being a single large insertion coding for IQ domains. Our results and evolutionary considerations suggest that brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells.     

Magnetar-like X-ray bursts from an anomalous X-ray pulsar

Anomalous X-ray pulsars (AXPs) are a class of rare X-ray emitting pulsars whose energy source has been perplexing for some 20 years. Unlike other X-ray emitting pulsars, AXPs cannot be powered by rotational energy or by accretion of matter from a binary companion star, hence the designation 'anomalous'. Many of the rotational and radiative properties of the AXPs are strikingly similar to those of another class of exotic objects, the soft-gamma-ray repeaters (SGRs). But the defining property of the SGRs--their low-energy-gamma-ray and X-ray bursts--has not hitherto been observed for AXPs. Soft-gamma-ray repeaters are thought to be 'magnetars', which are young neutron stars whose emission is powered by the decay of an ultra-high magnetic field; the suggestion that AXPs might also be magnetars has been controversial. Here we report two X-ray bursts, with properties similar to those of SGRs, from the direction of the anomalous X-ray pulsar 1E1048.1 - 5937. These events imply a close relationship (perhaps evolutionary) between AXPs and SGRs, with both being magnetars.     

A giant gamma-ray flare from the magnetar SGR 1806-20

Two classes of rotating neutron stars-soft gamma-ray repeaters (SGRs) and anomalous X-ray pulsars-are magnetars, whose X-ray emission is powered by a very strong magnetic field (B approximately 10(15) G). SGRs occasionally become 'active', producing many short X-ray bursts. Extremely rarely, an SGR emits a giant flare with a total energy about a thousand times higher than in a typical burst. Here we report that SGR 1806-20 emitted a giant flare on 27 December 2004. The total (isotropic) flare energy is 2 x 10(46) erg, which is about a hundred times higher than the other two previously observed giant flares. The energy release probably occurred during a catastrophic reconfiguration of the neutron star's magnetic field. If the event had occurred at a larger distance, but within 40 megaparsecs, it would have resembled a short, hard gamma-ray burst, suggesting that flares from extragalactic SGRs may form a subclass of such bursts.     

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.