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Sudipto Roy, Carol Wicking, Carsten Bergmann and colleagues report that mutations in DZIP1L cause autosomal recessive polycystic kidney disease (ARPKD). Through studies of mouse and zebrafish models of DZIP1L loss of function, the authors demonstrate that DZIP1L is required for proper function of the periciliary diffusion barrier. Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1 , has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L , which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L -mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.

Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b 0,+ transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b 0,+ AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.

Jaonna Jen and colleagues identify mutations in EXOSC3 , encoding a core RNA exosome component, causing pontocerebellar hypoplasia type 1 (PCH1), a recessive disorder with heterogeneous defects in brain development. Nine out of 13 individuals diagnosed with PCH1 had missense, frameshift or exon-skipping mutations in EXOSC3 , suggesting a critical role of RNA metabolism in normal brain development. RNA exosomes are multi-subunit complexes conserved throughout evolution 1 and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability 2 . By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596) 3 , 4 , 5 , 6 . We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

Shireen Lamandé and colleagues report mutations in TRPV4 in familial digital arthropathy-brachydactyly (FDAB), which is characterized by osteoarthropathy of the fingers and toes. TRPV4 is a cation channel, and functional experiments suggest mutant proteins are not localized properly to the cell surface. Familial digital arthropathy-brachydactyly (FDAB) is a dominantly inherited condition that is characterized by aggressive osteoarthropathy of the fingers and toes and consequent shortening of the middle and distal phalanges 1 . Here we show in three unrelated families that FDAB is caused by mutations encoding p.Gly270Val, p.Arg271Pro and p.Phe273Leu substitutions in the intracellular ankyrin-repeat domain of the cation channel TRPV4. Functional testing of mutant TRPV4 in HEK-293 cells showed that the mutant proteins have poor cell-surface localization. Calcium influx in response to the synthetic TRPV4 agonists GSK1016790A and 4αPDD was significantly reduced, and mutant channels did not respond to hypotonic stress. Others have shown that gain-of-function TRPV4 mutations cause skeletal dysplasias and peripheral neuropathies 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . Our data indicate that TRPV4 mutations that reduce channel activity cause a third phenotype, inherited osteoarthropathy, and show the importance of TRPV4 activity in articular cartilage homeostasis. Our data raise the possibility that TRPV4 may also have a role in age- or injury-related osteoarthritis.

Aggressive behavior is associated with dysfunctional frontolimbic emotion regulation circuits. Recent findings suggest serotonin as a primary transmitter for prefrontal amygdala control. However, the association between serotonin levels, amygdala regulation, and aggression is still a matter of debate. Neurobehavioral models furthermore suggest a possible mediating influence of the monoamine oxidase A gene ( ) on this brain-behavior relationship, with carriers of low expressing allele varieties being a risk group for aggression. In the present study, we investigated the influence of brain serotonin modulation and genotype on functional amygdala connectivity during aggressive behavior. Modulation of serotonergic neurotransmission with acute tryptophan depletion (ATD) and placebo were administered in a double-blind, cross-over design in 38 healthy male participants. Aggressive behavior was modeled in a violent video game during simultaneous assessment of brain activation with functional magnetic resonance imaging (fMRI). Trait aggression was measured with the Buss-Perry Aggression Questionnaire (BP-AQ), and genotypes were assessed from blood samples. Voxel-wise functional connectivity with anatomically defined amygdala was calculated from the functional data. Tryptophan depletion with ATD reduced aggression-specific amygdala connectivity with bilateral supramarginal gyrus. Moreover, ATD impact was associated with trait aggression and genotype in prefrontal cortex regions. In summary, serotonergic corticolimbic projections contribute to aggressive behavior. Genotype-specific vulnerability of frontolimbic projections may underlie the elevated risk in low expressing allele carriers.

Germ-line mutations are common in familial glomus tumors, which include pheochromocytomas and paragangliomas. This study examined whether unsuspected germ-line mutations in four genes (the proto-oncogene RET, the gene associated with von Hippel–Lindau disease [ VHL ], the gene for succinate dehydrogenase subunit D [ SDHD ], and the gene for succinate dehydrogenase subunit B [ SDHB ]) might account for some cases of apparently nonfamilial, nonsyndromic pheochromocytoma. Sixty-six of 271 patients with apparently sporadic pheochromocytoma had mutations in one of these four genes — 30 in VHL, 13 in RET, 11 in SDHD, and 12 in S DHB . It is becoming increasingly apparent that tumors of a single histologic type are heterogeneous in their natural history, prognosis, and response to treatment. Tumors such as pheochromocytomas and paragangliomas may also display important molecular differences and lend themselves to genetic analysis. It is a widespread assumption that most pheochromocytomas are sporadic and only about 10 percent are hereditary. 1 When hereditary, pheochromocytoma can be a component of multiple endocrine neoplasia type 2 (MEN-2), caused by mutations of the RET gene; von Hippel–Lindau disease, caused by mutations of the VHL gene; and, rarely, neurofibromatosis type 1. 2 – 5 Recently, mutations of the gene . . .

Recent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be overrepresented in patients suffering from bipolar disorder, schizophrenia or major depression. While the functions underlying the pathophysiology of these psychiatric disorders are yet unknown, impaired performance in verbal fluency tasks is an often replicated finding. We investigated the influence of the rs1006737 single nucleotide polymorphism (SNP) on verbal fluency and its neural correlates. Brain activation was measured with functional magnetic resonance imaging (fMRI) during a semantic verbal fluency task in 63 healthy male individuals. They additionally performed more demanding verbal fluency tasks outside the scanner. All subjects were genotyped for CACNA1C rs1006737. For the behavioral measures outside the scanner, rs1006737genotype had an effect on semantic but not on lexical verbal fluency with decreased performance in risk-allele carriers. In the fMRI experiment, while there were no differences in behavioural performance, increased activation in the left inferior frontal gyrus as well as the left precuneus was found in risk-allele carriers in the semantic verbal fluency task. The rs1006737 variant does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in bipolar disorder, schizophrenia and major depression and may explain some of the cognitive and brain activation variation found in these disorders.

Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation 1 . We mapped the disease-associated locus to chromosome 15q14–21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues 2 , 3 , 4 , 5 . Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1 −/− mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities 6 , 7 , had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.

In order to assess the feasibility of amplicon-based parallel next generation sequencing (NGS) for the diagnosis of myeloproliferative neoplasms (MPN), we investigated multiplex-PCR of 212 amplicons covering genomic mutational hotspots in 48 cancer-related genes. Samples from 64 patients with MPN and five controls as well as seven (myeloid) cell lines were analyzed. Healthy donor and reactive erythrocytosis samples showed several frequent single-nucleotide polymorphisms (SNPs) but no known pathogenic mutation. Sequencing of the cell lines confirmed the presence of the known mutations. In the patient samples, JAK2 V617F was present in all PV, 4 of 10 ET, and 16 of 19 MF patients. The JAK2 V617F allele burden was different in the three groups (ET, 33+/-22%; PV 48+/-28% and MF 68+/- 29%). Further analysis detected both previously described and undescribed mutations (i.e., G12V NRAS, IDH1 R132H, E255G ABL, and V125G IDH1 mutations). One patient with lymphoid BC/Ph+ ALL who harbored a T315I ABL mutation and was treated with ponatinib was found to have developed a newly acquired V216M TP53 mutation (12% of transcripts) when becoming resistant to ponatinib. Ponatinib led to a decrease of ABL T315I positive transcripts from 47% before ponatinib treatment to 16% at the time of ponatinib resistance in this patient, suggesting that both TP53 and ABL mutations were present in the same clone and that the newly acquired TP53 mutation might have caused ponatinib resistance in this patient. In conclusion, amplicon-sequencing-based NGS allows simultaneous analysis of multiple MPN associated genes for diagnosis and during treatment and measurement of the mutant allele burden.