BACKGROUND Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy). METHODS Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice. RESULTS Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting. CONCLUSIONS Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation.

Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia.

Facial recognition is central to the diagnosis of many syndromes, and craniofacial patterns may reflect common etiologies. In the pleiotropic Bardet-Biedl syndrome (BBS), a primary ciliopathy with intraflagellar transport dysfunction, patients have a characteristic facial ''gestalt'' that dysmorphologists have found difficult to characterize. Here, we use dense surface modeling (DSM) to reveal that BBS patients and mouse mutants have mid-facial defects involving homologous neural crest-derived structures shared by zebrafish morphants. These defects of the craniofacial (CF) skeleton arise from aberrant cranial neural crest cell (NCC) migration. These effects are not confined to the craniofacial region, but vagal-derived NCCs fail to populate the enteric nervous system, culminating in disordered gut motility. Furthermore, morphants display hallmarks of disrupted Sonic Hedgehog (Shh) signaling from which NCCs take positional cues. We propose a model whereby Bbs proteins modulate NCC migration, contributing to craniofacial morphogenesis and development of the enteric nervous system. These migration defects also explain the association of Hirschsprung's disease (HD) with BBS. Moreover, this is a previously undescribed method of using characterization of facial dysmorphology as a basis for investigating the pathomechanism of CF development in dysmorphic syndromes.sonic hedgehog ͉ Wnt ͉ cilia ͉ cell migration R ecognition of the facial ''gestalt'' is central to diagnosis of many genetic disorders, but the great variability of features often hinders successful classification (1). Recently, noninvasive 3D surface imaging has characterized dysmorphology in syndromes (2, 3). None, however, has been used to either define subtle facial dysmorphism or aid investigation of mechanisms for craniofacial dysmorphology.Bardet-Biedl syndrome (BBS) causes retinal degeneration, postaxial polydactyly, obesity, renal dysfunction, and cognitive impairment. Twelve BBS genes (BBS1-BBS12) have been discovered, and pathogenesis lies in primary cilia dysfunction (4). BBS4, BBS6, and BBS8 (investigated in this study) are expressed in ciliated epithelia and localize to the centrosome and basal bodies of ciliated cells (5-7). Subtle craniofacial abnormalities in patients have been reported (8-10). Among the many additional features of BBS is Hirschsprung's disease (HD), a disorder of the enteric nervous system (ENS) (11).Streams of neural crest cells (NCCs) from the caudal brain form most of the craniofacial (CF) skeleton (see ref. 12 for review). Cranial NCCs (CNCC) follow defined paths to populate the frontonasal prominence and branchial arch mesenchyme. Here, they proliferate and differentiate into structures of the face and cranium. Sonic Hedgehog (Shh) expressed in the ventral brain and oral ectoderm is essential for the formation of most facial structures (12). Shh-deficient mice have severe loss of craniofacial bones, and, in humans, SHH mutations cause midline CF defects with holoprosencephaly (HPE) (12).The ENS regulates gastrointestina...

Over the last 5 years, disorders of nonmotile cilia have come of age and their study has contributed immeasurably to our understanding of cell biology and human genetics. This review summarizes the main features of the ciliopathies, their underlying genetics, and the functions of the proteins involved. We describe some of the key findings in the field, including new animal models, the role of ciliopathy proteins in signaling pathways and development, and the unusual genetics of these diseases. We also discuss the therapeutic potential for these diseases and finally, discuss important future work that will extend our understanding of this fascinating organelle and its associated pathologies. Genet Med 2009:11(6):386 -402.