Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.     

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ～5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.     

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.     

Burrowing Owl nest success and burrow longevity in north central Oregon

We studied nest success, burrow longevity, and rates of burrow reuse for a migratory population of Burrowing Owl ( Athene cunicularia ) in north central Oregon from 1995 to 1997. Nest success varied annually from 50% to 67%. Principal causes of nest failure were desertion (26%) and depredation by badgers ( Taxidea taxus ; 13%). Reuse of available nest and satellite burrows in subsequent years was 87% in 1996 and 57% in 1997. Reuse was highest at burrows in sandy soils, which may indicate that nest-site availability is a limiting factor in sandier soil types. Trampling by livestock resulted in the loss of 24% of all burrows between one season and the next, and natural erosion resulted in closure of 17%. Both causes of burrow failure occurred more frequently in soils with a sand component due to their friable nature. We recommend that habitat used by livestock be evaluated for use by Burrowing Owls, that occupied areas be managed to minimize destruction of burrows by livestock, and that predator-control efforts be revised to exclude mortality of badgers.     

Bending-related faulting and mantle serpentinization at the Middle America trench

The dehydration of subducting oceanic crust and upper mantle has been inferred both to promote the partial melting leading to arc magmatism and to induce intraslab intermediate-depth earthquakes, at depths of 50-300 km. Yet there is still no consensus about how slab hydration occurs or where and how much chemically bound water is stored within the crust and mantle of the incoming plate. Here we document that bending-related faulting of the incoming plate at the Middle America trench creates a pervasive tectonic fabric that cuts across the crust, penetrating deep into the mantle. Faulting is active across the entire ocean trench slope, promoting hydration of the cold crust and upper mantle surrounding these deep active faults. The along-strike length and depth of penetration of these faults are also similar to the dimensions of the rupture area of intermediate-depth earthquakes.