The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin

Nephronophthisis, the most common genetic cause of chronic renal failure in children, is a progressive tubulo-interstitial kidney disorder that is inherited as an autosomal recessive trait. The disease is characterized by polyuria, growth retardation and deterioration of renal function during childhood or adolescence. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (Senior-L?ken syndrome) and ocular motor apraxia (Cogan syndrome). Three loci are associated with the juvenile, infantile and adolescent forms, on chromosomes 2q13 (NPHP1; refs 5,6), 9q22 (NPHP2; ref. 7) and 3q21 (NPHP3; ref. 8), respectively. NPHP1, the only gene identified so far, encodes nephrocystin, which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion. Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14). We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region. This allowed us to reduce the NPHP4 interval to a one centimorgan interval between D1S2795 and D1S2870, which contains six genes. We identified five different mutations in one of these genes, designated NPHP4, in unrelated individuals with nephronophthisis. The NPHP4 gene encodes a 1,250-amino acid protein of unknown function that we named nephrocystin-4. We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway.     

Remains of Homo erectus from Bouri, Middle Awash, Ethiopia

The genesis, evolution and fate of Homo erectus have been explored palaeontologically since the taxon's recognition in the late nineteenth century. Current debate is focused on whether early representatives from Kenya and Georgia should be classified as a separate ancestral species ('H. ergaster'), and whether H. erectus was an exclusively Asian species lineage that went extinct. Lack of resolution of these issues has obscured the place of H. erectus in human evolution. A hominid calvaria and postcranial remains recently recovered from the Dakanihylo Member of the Bouri Formation, Middle Awash, Ethiopia, bear directly on these issues. These approximately 1.0-million-year (Myr)-old Pleistocene sediments contain abundant early Acheulean stone tools and a diverse vertebrate fauna that indicates a predominantly savannah environment. Here we report that the 'Daka' calvaria's metric and morphological attributes centre it firmly within H. erectus. Daka's resemblance to Asian counterparts indicates that the early African and Eurasian fossil hominids represent demes of a widespread palaeospecies. Daka's anatomical intermediacy between earlier and later African fossils provides evidence of evolutionary change. Its temporal and geographic position indicates that African H. erectus was the ancestor of Homo sapiens.     

Evolution of the mammalian G protein alpha subunit multigene family.

Heterotrimeric guanine nucleotide binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. The multigene family of G protein alpha subunits, which interact with receptors and effectors, exhibit a high level of sequence diversity. In mammals, 15 G alpha subunit genes can be grouped by sequence and functional similarities into four classes. We have determined the murine chromosomal locations of all 15 G alpha subunit genes using an interspecific backcross derived from crosses of C57BL/6J and Mus spretus mice. These data, in combination with mapping studies in humans, have provided insight into the events responsible for generating the genetic diversity found in the mammalian alpha subunit genes and a framework for elucidating the role of the G alpha subunits in disease.     

The participation of the adrenal and thyroid in fat metabolism in hypophysectomized baboons (Papio ursinus)

Zusammenfassung 1. Im Gegensatz zum Hund entwickelt sich beim Pavian keine Fettleber nach Hypophysektomie oder Thyreoidektomie oder nach einer Kombination dieser beiden Eingriffe.2. Thyroxin wirkt als Antagonist hemmend auf die Fettbildung, die durch Cortison beim hypophysektomierten Pavian angeregt wird.3. Starke Leberverfettung entsteht bei hypophysektomierten Pavianen nach gleichzeitiger Entziehung von Cortison und Thyroxin.     

A reappraisal of the hormonal regulation of larval fat body histolysis in femaleDrosophila melanogaster

The histolysis of larval fat body cells in adult femaleDrosophila melanogaster was examined in wild type and mutant animals. The fat body cells of wild type (Canton-S),apterous ^56f homozygotes,apterous ^78jts homozygotes and heterozygotes,apterous ⁴/+, ecdysoneless¹ homozygotes and heterozygotes all underwent histolysis normally during the 72 h following adult eclosion. Only in the case ofap ⁴/ap⁴ adults did the cells fail to histolyze normally. The fat body cells of both diapausing and non-diapausing wild type females underwent histolysis at the same rate. Attempts to demonstrate histolysis in vitro were unsuccessful, even in the presence of juvenile hormones (JHs), larval ring glands, or adult ovaries. In all strains other than theap ⁴ homozygotes, a significant proportion of larval fat body cells were dead at any time while theap ⁴/ap⁴ animals, almost all cells remained viable. It is postulated that fat body cell lysis following eclosion is not a JH-mediated event, but is elicited by an as yet unidentified factor(s), possibly originating in the ovary.     

Generation of end-inhibition in the visual cortex via interlaminar connections

To understand the mechanisms by which the receptive field properties of visual cortical cells are generated, one must consider both the thalamic input to the cortex and the intrinsic cortical connections. In the cat striate cortex, layer 4 is the main recipient of input from the lateral geniculate nucleus, yet the cells in that layer possess several receptive field properties that are distinct from the geniculate input, including orientation specificity, binocularity, directionality and end-inhibition, the last of which allows cells to respond to edges of a restricted length. These properties could be generated by connections within the layer, by its input from the claustrum or by the massive projection that layer 4 receives from layer 6. In the present study, we attempted to determine the functional role of the layer 6 to layer 4 projection by reversible inactivation of layer 6 using the inhibitory transmitter gamma-aminobutyric acid (GABA). After inactivating layer 6, cells in layer 4 lost end-inhibition. Cells in layer 2 + 3, which receive their principal input from layer 4, were similarly affected. The elimination of end-inhibition was specific, other receptive field properties, such as direction selectivity or orientation specificity, remaining intact.