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BackgroundJoubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene–phenotype associations in JS.MethodsWe sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.ResultsWe identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a ‘pure JS’ phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.ConclusionsThis work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

IPEX is a fatal disorder characterized by immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance (MIM 304930). We present genetic evidence that different mutations of the human gene FOXP3 , the ortholog of the gene mutated in scurfy mice ( Foxp3 ), causes IPEX syndrome. Recent linkage analysis studies mapped the gene mutated in IPEX to an interval of 17–20-cM at Xp11.23–Xq13.3 (refs. 1 , 2 ).

ObjectiveTo identify genetic causes of COACH syndromeBackgroundCOACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD).MethodsIn a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced.Results19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%).ConclusionsMutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.

Deregulation of tight junction (TJ) proteins and the associated disruption of TJ function has been demonstrated to play a role in the development of endometrial cancer. In the current study, we have shown overexpression of claudin-3 and -4 mRNA (by RT-PCR) and protein (by immunoblotting) in a panel of 9 human endometrial cancer cell lines. To further expand our understanding of the complex role of TJ deregulation in endometrial cancer, we also investigated the expression of 84 TJ and TJ-associated genes (encoding the array of proteins that function within the TJ network from the membrane to nuclear signaling pathways) by microarray analysis. Consistent with the claudin-3 and -4 RT-PCR and immunoblot findings described above, we observed overexpression of the claudin-3 and -4 genes by microarray analysis. Further, we observed overexpression of an additional three genes in 8 of the 9 endometrial cancer cell lines: OCLN (occludin), F11R (JAM-A) and TJP3 (ZO-3). OCLN and F11R encode integral membrane proteins whereas TJP3 encodes a cytosolic scaffolding protein that indirectly links membrane TJ proteins to the actin cytoskeleton and cell signaling pathways. Our data suggest that the structural disruption of TJs coupled with the downstream deregulation of signaling pathways involved in cellular proliferation and migration may contribute to the development of endometrial cancer.

Background: Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1). Methods: We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis. Results: We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions. Conclusions: Overall, 11% of subjects had AHI1 mutations, while ∼2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype-phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.

BackgroundGenomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype.Methods and resultsBased on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA.ConclusionsTogether with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.

X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry technique, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.

Additive manufacturing (AM) processes are proving to be a disruptive technology and are grabbing the attention of the propulsion industry. AM-related advancements in new industries, supply chains, design opportunities, and novel materials are increasing at a rapid pace. The goal of this text is to provide an overview of the practical concept-to-utilization lifecycle in AM for propulsion applications.As with any new process, it's tempting to get caught up in the excitement of AM and its application and to give little forethought to the potential economic and technical challenges. This text is intended to help AM adopters to be intentional as they apply these technologies, and to understand the basis for the lifecycle of AM components. It is a practical guide based on lessons learned and experiences with both successes and in failures in AM. The organization of this text seeks to guide an engineer through the intertwined basics, regarding design and implementation, as they begin their journey into AM. The book is also relevant for veteran AM users as a reference. While AM is still in the development phase and continues to evolve, the fundamental lessons learned remain of great value even as forthcoming technology emerges. While many metal AM processes are referenced, the book focuses on those with more industry maturity, including powder bed fusion and directed energy deposition.

Senataxin mutations are the molecular basis of two distinct syndromes: (1) ataxia oculomotor apraxia type 2 (AOA2) and (2) juvenile amyotrophic lateral sclerosis 4 (ALS4). The authors describe clinical and molecular genetic studies of mother and daughter who display symptoms of cerebellar ataxia/atrophy, oculomotor defects, and tremor. Both patients share Senataxin mutations N603D and Q653K in cis (N603D-Q653K), adjacent to an N-terminal domain thought to function in protein-protein interaction. The N-terminal and helicase domains appear to harbor missense mutation clusters associated with AOA2 and ALS4. Working synergistically, the N603D-Q653K mutations may confer a partial dominant negative effect, acting on the senataxin N-terminal, further expanding the phenotypic spectrum associated with Senataxin mutations.

Abstract The biotic resistance hypothesis (BRH) was proposed to explain why intermediate disturbances lead to greater resistance to non-native invasions proposing communities that are more diverse provide greater resistance. However, several empirical data sets have rejected the BRH because native and non-native species richness often have a positive relation. We tested the BRH in a mature loblolly pine (Pinus taeda) forest with a gradient of disturbance intensities including canopy reduction, canopy reduction + fire, and canopy reduction + herbicide and fire. We analyzed data from the study using a combination of Pearson’s correlation and beta regressions. Using species richness, we too would reject BRH because of a positive correlation in species richness between native and non-native plants. However, native species abundance was greatest, and non-native species abundance was lowest following intermediate disturbances. Further, native and non-native species abundances were negatively correlated in a quadratic relation across disturbance intensities, suggesting that native species abundance, rather than richness, may be the mechanism of resistance to non-native invasions. We propose that native species abundance regulates resistance to non-native invasions and that intermediate disturbances provide the greatest resistance because they promote the greatest native species abundance.