Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.     

Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.     

Apolipoprotein L-I is the trypanosome lytic factor of human serum

Human sleeping sickness in east Africa is caused by the parasite Trypanosoma brucei rhodesiense. The basis of this pathology is the resistance of these parasites to lysis by normal human serum (NHS). Resistance to NHS is conferred by a gene that encodes a truncated form of the variant surface glycoprotein termed serum resistance associated protein (SRA). We show that SRA is a lysosomal protein, and that the amino-terminal alpha-helix of SRA is responsible for resistance to NHS. This domain interacts strongly with a carboxy-terminal alpha-helix of the human-specific serum protein apolipoprotein L-I (apoL-I). Depleting NHS of apoL-I, by incubation with SRA or anti-apoL-I, led to the complete loss of trypanolytic activity. Addition of native or recombinant apoL-I either to apoL-I-depleted NHS or to fetal calf serum induced lysis of NHS-sensitive, but not NHS-resistant, trypanosomes. Confocal microscopy demonstrated that apoL-I is taken up through the endocytic pathway into the lysosome. We propose that apoL-I is the trypanosome lytic factor of NHS, and that SRA confers resistance to lysis by interaction with apoL-I in the lysosome.     

A very energetic supernova associated with the gamma-ray burst of 29 March 2003

Over the past five years evidence has mounted that long-duration (>2 s) gamma-ray bursts (GRBs)-the most luminous of all astronomical explosions-signal the collapse of massive stars in our Universe. This evidence was originally based on the probable association of one unusual GRB with a supernova, but now includes the association of GRBs with regions of massive star formation in distant galaxies, the appearance of supernova-like 'bumps' in the optical afterglow light curves of several bursts and lines of freshly synthesized elements in the spectra of a few X-ray afterglows. These observations support, but do not yet conclusively demonstrate, the idea that long-duration GRBs are associated with the deaths of massive stars, presumably arising from core collapse. Here we report evidence that a very energetic supernova (a hypernova) was temporally and spatially coincident with a GRB at redshift z = 0.1685. The timing of the supernova indicates that it exploded within a few days of the GRB, strongly suggesting that core-collapse events can give rise to GRBs, thereby favouring the 'collapsar' model.     

Motor neuron columnar fate imposed by sequential phases of Hox-c activity

The organization of neurons into columns is a prominent feature of central nervous system structure and function. In many regions of the central nervous system the grouping of neurons into columns links cell-body position to axonal trajectory, thus contributing to the establishment of topographic neural maps. This link is prominent in the developing spinal cord, where columnar sets of motor neurons innervate distinct targets in the periphery. We show here that sequential phases of Hox-c protein expression and activity control the columnar differentiation of spinal motor neurons. Hox expression in neural progenitors is established by graded fibroblast growth factor signalling and translated into a distinct motor neuron Hox pattern. Motor neuron columnar fate then emerges through cell autonomous repressor and activator functions of Hox proteins. Hox proteins also direct the expression of genes that establish motor topographic projections, thus implicating Hox proteins as critical determinants of spinal motor neuron identity and organization.     

Non-thermal melting in semiconductors measured at femtosecond resolution

Ultrafast time-resolved optical spectroscopy has revealed new classes of physical, chemical and biological reactions, in which directed, deterministic motions of atoms have a key role. This contrasts with the random, diffusive motion of atoms across activation barriers that typically determines kinetic rates on slower timescales. An example of these new processes is the ultrafast melting of semiconductors, which is believed to arise from a strong modification of the inter-atomic forces owing to laser-induced promotion of a large fraction (10% or more) of the valence electrons to the conduction band. The atoms immediately begin to move and rapidly gain sufficient kinetic energy to induce melting--much faster than the several picoseconds required to convert the electronic energy into thermal motions. Here we present measurements of the characteristic melting time of InSb with a recently developed technique of ultrafast time-resolved X-ray diffraction that, in contrast to optical spectroscopy, provides a direct probe of the changing atomic structure. The data establish unambiguously a loss of long-range order up to 900 A inside the crystal, with time constants as short as 350 femtoseconds. This ability to obtain the quantitative structural characterization of non-thermal processes should find widespread application in the study of ultrafast dynamics in other physical, chemical and biological systems.     

A conserved sorting-associated protein is mutant in chorea-acanthocytosis

Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.     

CARD15 mutations in Blau syndrome

Lack of a maternal contribution to the genome at the imprinted domain on proximal chromosome 15 causes Angelman syndrome (AS) associated with neurobehavioral anomalies that include severe mental retardation, ataxia and epilepsy. Although AS patients have infrequent mutations in the gene encoding an E6-AP ubiquitin ligase required for long-term synaptic potentiation (LTP), most cases are attributed to de novo maternal deletions of 15q11-q13. We report here that a novel maternally expressed gene, ATP10C, maps within the most common interval of deletion and that ATP10C expression is virtually absent from AS patients with imprinting mutations, as well as from patients with maternal deletions of 15q11-q13.     

Crackling noise

Crackling noise arises when a system responds to changing external conditions through discrete, impulsive events spanning a broad range of sizes. A wide variety of physical systems exhibiting crackling noise have been studied, from earthquakes on faults to paper crumpling. Because these systems exhibit regular behaviour over a huge range of sizes, their behaviour is likely to be independent of microscopic and macroscopic details, and progress can be made by the use of simple models. The fact that these models and real systems can share the same behaviour on many scales is called universality. We illustrate these ideas by using results for our model of crackling noise in magnets, explaining the use of the renormalization group and scaling collapses, and we highlight some continuing challenges in this still-evolving field.