Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia

The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4alpha-phorbol 12,13-didecanoate (4alphaPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.     

Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture

Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development.     

Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity

Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2. Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4(+) CD25(+) regulatory T cells, which are critical for maintaining immune homeostasis.     

Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo.

Extracellular elastic fibres provide mechanical elasticity to tissues and contribute towards the processes of organ remodelling by affecting cell-cell signalling. The formation of elastic fibres requires the assembly and crosslinking of tropoelastin monomers, and organization of the resulting insoluble elastin matrix into functional fibres. The molecules and mechanisms involved in this process are unknown. Fibulin-5 (also known as EVEC/DANCE) is an extracellular matrix protein abundantly expressed in great vessels and cardiac valves during embryogenesis, and in many adult tissues including the aorta, lung, uterus and skin, all of which contain abundant elastic fibres. Here we show that fibulin-5 is a calcium-dependent, elastin-binding protein that localizes to the surface of elastic fibres in vivo. fibulin-5-/- mice develop marked elastinopathy owing to the disorganization of elastic fibres, with resulting loose skin, vascular abnormalities and emphysematous lung. This phenotype, which resembles the cutis laxa syndrome in humans, reveals a critical function for fibulin-5 as a scaffold protein that organizes and links elastic fibres to cells. This function may be mediated by the RGD motif in fibulin-5, which binds to cell surface integrins, and the Ca2+-binding epidermal growth factor (EGF) repeats, which bind elastin.     

Primary forests are irreplaceable for sustaining tropical biodiversity

Human-driven land-use changes increasingly threaten biodiversity, particularly in tropical forests where both species diversity and human pressures on natural environments are high. The rapid conversion of tropical forests for agriculture, timber production and other uses has generated vast, human-dominated landscapes with potentially dire consequences for tropical biodiversity. Today, few truly undisturbed tropical forests exist, whereas those degraded by repeated logging and fires, as well as secondary and plantation forests, are rapidly expanding. Here we provide a global assessment of the impact of disturbance and land conversion on biodiversity in tropical forests using a meta-analysis of 138 studies. We analysed 2,220 pairwise comparisons of biodiversity values in primary forests (with little or no human disturbance) and disturbed forests. We found that biodiversity values were substantially lower in degraded forests, but that this varied considerably by geographic region, taxonomic group, ecological metric and disturbance type. Even after partly accounting for confounding colonization and succession effects due to the composition of surrounding habitats, isolation and time since disturbance, we find that most forms of forest degradation have an overwhelmingly detrimental effect on tropical biodiversity. Our results clearly indicate that when it comes to maintaining tropical biodiversity, there is no substitute for primary forests.