Identification of the gene that, when mutated, causes the human obesity syndrome BBS4

Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4.     

Colloid science: non-spherical bubbles

Surface tension gives gas bubbles their perfect spherical shape by minimizing the surface area for a given volume. Here we show that gas bubbles and liquid drops can exist in stable, non-spherical shapes if the surface is covered, or 'armoured', with a close-packed monolayer of particles. When two spherical armoured bubbles are fused, jamming of the particles on the interface supports the unequal stresses that are necessary to stabilize a non-spherical shape.     

A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M

Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition. Nine genes involved in Fanconi anemia have been identified; their products participate in a DNA damage-response network involving BRCA1 and BRCA2 (refs. 2,3). We previously purified a Fanconi anemia core complex containing the FANCL ubiquitin ligase and six other Fanconi anemia-associated proteins. Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the Fanconi anemia DNA damage-response pathway. Here we show that another component of this complex, FAAP250, is mutant in individuals with Fanconi anemia of a new complementation group (FA-M). FAAP250 or FANCM has sequence similarity to known DNA-repair proteins, including archaeal Hef, yeast MPH1 and human ERCC4 or XPF. FANCM can dissociate DNA triplex, possibly owing to its ability to translocate on duplex DNA. FANCM is essential for monoubiquitination of FANCD2 and becomes hyperphosphorylated in response to DNA damage. Our data suggest an evolutionary link between Fanconi anemia-associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA.     

Diet and the evolution of human amylase gene copy number variation

Starch consumption is a prominent characteristic of agricultural societies and hunter-gatherers in arid environments. In contrast, rainforest and circum-arctic hunter-gatherers and some pastoralists consume much less starch. This behavioral variation raises the possibility that different selective pressures have acted on amylase, the enzyme responsible for starch hydrolysis. We found that copy number of the salivary amylase gene (AMY1) is correlated positively with salivary amylase protein level and that individuals from populations with high-starch diets have, on average, more AMY1 copies than those with traditionally low-starch diets. Comparisons with other loci in a subset of these populations suggest that the extent of AMY1 copy number differentiation is highly unusual. This example of positive selection on a copy number-variable gene is, to our knowledge, one of the first discovered in the human genome. Higher AMY1 copy numbers and protein levels probably improve the digestion of starchy foods and may buffer against the fitness-reducing effects of intestinal disease.     

Microbial carcinogenic toxins and dietary anti-cancer protectants

Several toxins are known which account for the ability of some bacteria to initiate or promote carcinogenesis. These ideas are summarised and evidence is discussed for more specific mechanisms involving chymotrypsin and the bacterial chymotryptic enzyme subtilisin. Subtilisin and Bacillus subtilis are present in the gut and environment and both are used commercially in agriculture, livestock rearing and meat processing. The enzymes deplete cells of tumour suppressors such as deleted in colorectal cancer (DCC) and neogenin, so their potential presence in the food chain might represent an important link between diet and cancer. Over-eating increases secretion of chymotrypsin which is absorbed from the gut and could contribute to several forms of cancer linked to obesity. Inhibition of these serine proteases by Bowman–Birk inhibitors in fruit and vegetables could account for some of the protective effects of a plant-rich diet. These interactions represent previously unknown non-genetic mechanisms for the modification of tumour suppressor proteins and provide a plausible explanation contributing to both the pro-oncogenic effects of meat products and the protective activity of a plant-rich diet. The data suggest that changes to farming husbandry and food processing methods to remove these sources of extrinsic proteases might significantly reduce the incidence of several cancers.     

Recent developments in neuropsychological endophenotypes for schizophrenia: Development of the MATRICS battery,liability syndromes and the near future

Cognitive deficits are now recognized widely as core features of schizophrenia, and as major contributors to the clinical outcome of the disorder. They are also studied widely as ‘endophenotypes’, reflecting a growing consensus that schizophrenia is a broader, more multidimensional illness than the diagnostic criteria required for its formal diagnosis. This evolving view of cognition underlies its utilization in recent initiatives for intervention and assessment in schizophrenia. Two of these initiatives ar...     

Is glutamic acid the pyramidal tract neurotransmitter?

Applied by microiontophoresis, 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) antagonized excitation by glutamic acid but not by acetylcholine of neurones in the rat cuneate nucleus. HA-966 blocked the short latency excitation of cuneate neurones following stimulation of the pyramidal tract on 28 of 40 cells (70%). Thus, glutamate or a related amino-acid may be the neurotransmitter released by pyramidal tract neurones.     

The effects of phenoxybenzamine on the aortic pressure-diameter relationship in dogs

Summary The normalized diameter (D/D_13.3 where D_13.3 equals D at 13.3 kPa under control conditions) was measured at selected pressure levels under different hemodynamic conditions. Hemorrhage caused the normalized diameter to decrease (–3.3%) when compared to control values at a given pressure. Volume expansion anda-blockade with phenoxybenzamine caused D/D_13.3 to increase (+3.3% and +8.5% respectively).This work was supported in part by PHS grant HL-23239 and a grant from the Central Ohio Heart Chapter of the American Heart Association. To whom reprint request should be addressed.     

Intron-dependent evolution of chicken glyceraldehyde phosphate dehydrogenase gene

The function of introns in the evolution of genes can be explained in at least two ways: either introns appeared late in evolution and therefore could not have participated in the construction of primordial genes, or RNA splicing and introns existed in the earliest organisms but were lost during the evolution of the modern prokaryotes. The latter alternative allows the possibility of intron participation in the formation of primordial genes before the divergence of modern prokaryotes and eukaryotes. Blake suggested that evidence for intron-facilitated evolution of a gene might be found by comparing the borders of functional protein domains with the placement of introns. We therefore examined glyceraldehyde phosphate dehydrogenase (GAPDH), a glycolytic enzyme, because it is the first protein for which the following data are available: X-ray crystallographic studies demonstrating structurally independent protein 'domains' which were highly conserved during the divergence of prokaryotes and eukaryotes; and a study of genomic organization which mapped introns in the gene. Sequencing of the chicken GAPDH gene revealed 11 introns. We report here that sites of three of the introns (IV, VI and XI) correspond closely with the borders of the NAD-binding, catalytic and helical tail domains of the enzyme, supporting the hypothesis that introns did have a role in the evolution of primitive genes. In addition, other biochemical and structural data were used to construct a model of the intron-mediated assembly of the GAPDH gene that explains the existence of 10 introns.