Association of variants in the CP, ATOX1 and COMMD1 genes with Wilson disease symptoms in Latvia

Funding Information: This study was partially financed by a grant of Riga Stradins University, Department of Doctoral studies and grant of Roche Academy. Funding Information: Funding . This study was partially financed by a grant of Riga Stradiņš University, Department of Doctoral studies and grant of Roche Academy. Publisher Copyright: © 2019 Zarina A, Tolmane I, Krumina Z, Tutane AI, Gailite L, published by Sciendo.Wilson's disease (WD) is a copper metabolism disorder, caused by allelic variants in the ATP7B gene. Wilson's disease can be diagnosed by clinical symptoms, increased copper and decreased cerulopasmin levels, which could all also be by other genetic variants beyond the ATP7B gene, e.g., disturbed ceruloplasmin biosynthesis can be caused by pathogenic allelic variants of the CP gene. Copper metabolism in the organism is affected by several molecules, but pathogenic variants and related phenotypes are described with COMMD1 and ATOX1 genes. The aim of the study was to test other genes, CP, ATOX1 and COMMD1, for possible influence to the manifestation of WD. Patients were enrolled on the basis of Leipzig's diagnostic criteria, 64 unrelated patients with confirmed WD. Direct sequencing of promoter region of the CP gene and ATOX1 and COMMD1 gene exons was conducted. Statistically significant differences were found between the two variants in the CP gene and the ATP7B genotype (rs66508328 variant AA genotype and the rs11708215 variant GG genotype) were more common in WD patients with an unconfirmed ATP7B genotype. One allelic (intronic) variant was found in the ATOX1 gene without causing the functional changes of the gene. Three allelic variants were identified in the COMMD1 gene. No statistically significant differences were found between allele and genotype frequencies and the first clinical manifestations of WD. Different variants of the CP gene contributed to a WD-like phenotype in clinically confirmed WD patients with neurological symptoms and without identified pathogenic variants in the ATP7B gene. Allelic variants in the ATOX1 and COMMD1 genes do not modify the clinical manifestation of WD in Latvian patients.publishersversionPeer reviewe

Clinical and Genetic Characterisation of Cystic Fibrosis Patients in Latvia : A Twenty-Five-Year Experience

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Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders. METHODS: Ninety-six CMT patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single molecule array (Simoa) NfL assay. RESULTS: The NfL concentration was significantly higher in the CMT patient group than in the controls (p<0.001). Of the CMT patients, ones with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. ROC analysis showed that an NfL concentration of 8.9 pg/mL could be used to discriminate CMT patients from controls, with an area under the curve of 0.881. CONCLUSIONS: Our study confirmed that the plasma NfL concentration is significantly higher in CMT patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT; however, several issues need to be addressed first

Hirnantia sagittifera

The brachiopod Hirnantia sagittifera (M’Coy) and trilobite morphs of the genus Mucronaspis from the topmost Ordovician Porkuni Stage of the central East Baltic are described and compared with those from the Hirnantian Stage of other regions. These important Hirnantian taxa occur in the Livonian Tongue of the Central Baltoscandian Facies Belt of the Baltic Basin, where the Porkuni Stage is represented by the non-graptolitic Kuldiga and Saldus formations. Hirnantia sagittifera appears in the lowermost part of the Porkuni Stage and is rather widely distributed in the basin in spite of its rare finds in each locality. Our study of trilobites of the genus Mucronaspis has enabled us to observe morphological changes in its exoskeleton in time and to identify a succession of five morphotypes (morphs). In some characteristics these morphs are similar to those of different alleged species of the genus Mucronaspis (M. olini, M. danai, M. ganabina, M. mucronata) but they cannot be definitely assigned to any of these species due to some variances. However, here for the first time a stratigraphically ordered collection is presented, which deserves attention in revising the taxonomy of highly variable Mucronaspis. The described brachiopods and trilobites occur mainly in the strata correlated with the Normalograptus extraordinarius graptolite Biozone. However, the uppermost finds of both taxa come from strata correlated with the N. persculptus Biozone

Kinase-activity-independent functions of atypical protein kinase C in Drosophila

Polarity of many cell types is controlled by a protein complex consisting of Bazooka/PAR-3 (Baz), PAR-6 and atypical protein kinase C (aPKC). In Drosophila, the Baz-PAR-6-aPKC complex is required for the control of cell polarity in the follicular epithelium, in ectodermal epithelia and neuroblasts. aPKC is the main signaling component of this complex that functions by phosphorylating downstream targets, while the PDZ domain proteins Baz and PAR-6 control the subcellular localization and kinase activity of aPKC. We compared the mutant phenotypes of an aPKC null allele with those of four novel aPKC alleles harboring point mutations that abolish the kinase activity or the binding of aPKC to PAR-6. We show that these point alleles retain full functionality in the control of follicle cell polarity, but produce strong loss-of-function phenotypes in embryonic epithelia and neuroblasts. Our data, combined with molecular dynamics simulations, show that the kinase activity of aPKC and its ability to bind PAR-6 are only required for a subset of its functions during development, revealing tissue-specific differences in the way that aPKC controls cell polarity

Association of variants in the CP, ATOX1 and COMMD1 genes with Wilson disease symptoms in Latvia

Wilson’s disease (WD) is a copper metabolism disorder, caused by allelic variants in the ATP7B gene. Wilson’s disease can be diagnosed by clinical symptoms, increased copper and decreased cerulopasmin levels, which could all also be by other genetic variants beyond the ATP7B gene, e.g., disturbed ceruloplasmin biosynthesis can be caused by pathogenic allelic variants of the CP gene. Copper metabolism in the organism is affected by several molecules, but pathogenic variants and related phenotypes are described with COMMD1 and ATOX1 genes. The aim of the study was to test other genes, CP, ATOX1 and COMMD1, for possible influence to the manifestation of WD. Patients were enrolled on the basis of Leipzig’s diagnostic criteria, 64 unrelated patients with confirmed WD. Direct sequencing of promoter region of the CP gene and ATOX1 and COMMD1 gene exons was conducted. Statistically significant differences were found between the two variants in the CP gene and the ATP7B genotype (rs66508328 variant AA genotype and the rs11708215 variant GG genotype) were more common in WD patients with an unconfirmed ATP7B genotype. One allelic (intronic) variant was found in the ATOX1 gene without causing the functional changes of the gene. Three allelic variants were identified in the COMMD1 gene. No statistically significant differences were found between allele and genotype frequencies and the first clinical manifestations of WD. Different variants of the CP gene contributed to a WD-like phenotype in clinically confirmed WD patients with neurological symptoms and without identified pathogenic variants in the ATP7B gene. Allelic variants in the ATOX1 and COMMD1 genes do not modify the clinical manifestation of WD in Latvian patients. (266 words

Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila

The specification of tissue size during development involves the coordinated action of many signalling pathways responding to organ-intrinsic signals, such as morphogen gradients, and systemic cues, such as nutrient status. The conserved Hippo (Hpo) pathway, which promotes both cell cycle exit and apoptosis, is a major determinant of size control.The pathway core is a kinase cassette, comprising the kinases Hpo and Warts (Wts) and the scaffold proteins Salvador (Sav) and Mats, which inactivates the pro-growth transcriptional co-activator Yorkie (Yki). We performed a split TEV-based genome-wide RNAi screen for modulators of Hpo signalling. We characterise the Drosophila salt-inducible kinases (Sik2 and Sik3) as negative regulators of Hpo signalling. Activated Sik kinases increase Yki target expression and promote tissue overgrowth through phosphorylation of Sav at Ser413. Since Sik kinases have been implicated in nutrient sensing, this suggests a link between the Hippo pathway and systemic growth control

Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population.

OBJECTIVE: Netherton syndrome (NS) (OMIM:256500) is a very rare autosomal recessive multisystem disorder mostly affecting ectodermal derivatives (skin and hair) and immune system. It is caused by biallelic loss-of-function variants in the SPINK5 gene, encoding the protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI). MATERIAL, METHODS AND RESULTS: Here, we describe NS clinical and genetic features of homogenous patient group: 9 individuals from 7 families with similar ethnic background and who have the same SPINK5 variant (NM_006846.4: c.1048C > T, p.(Arg350*)) in homozygous or compound heterozygous states, suggesting that it is a common founder variant in Latvian population. Indeed, we were able to show that the variant is common in general Latvian population, and it shares the same haplotype among the NS individual. It is estimated that the variant arose >1000 years ago. Clinically, all nine patients exhibited typical NS skin changes (scaly erythroderma, ichthyosis linearis circumflexa, itchy skin), except for one patient who has a different skin manifestation-epidermodysplasia. Additionally, we show that developmental delay, previously underrecognized in NS, is a common feature among these patients. CONCLUSIONS: This study shows that the phenotype of NS individuals with the same genotype is highly homogeneous

Plasma neurofilament light chain as a potential biomarker in Charcot‐Marie‐Tooth disease

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a chronic, slowly progressing disorder. The lack of specific disease progression biomarkers limits the execution of clinical trials. However, neurofilament light chain (NfL) has been suggested as a potential biomarker for peripheral nervous system disorders. METHODS: Ninety-six CMT patients and 60 healthy controls were enrolled in the study. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Blood plasma NfL concentrations were measured using the single molecule array (Simoa) NfL assay. RESULTS: The NfL concentration was significantly higher in the CMT patient group than in the controls (p<0.001). Of the CMT patients, ones with type CMTX1 had a higher NfL level than those in the two other analysed subgroups (CMT1A and other CMT types) (p=0.0498). The NfL concentration had a significant but weak correlation with the CMTNSv2 (rs =0.25, p=0.012). In one CMT patient with an extremely elevated NfL level, overlap with chronic inflammatory demyelinating polyneuropathy was suspected. ROC analysis showed that an NfL concentration of 8.9 pg/mL could be used to discriminate CMT patients from controls, with an area under the curve of 0.881. CONCLUSIONS: Our study confirmed that the plasma NfL concentration is significantly higher in CMT patients than in controls. Plasma NfL concentration was found to significantly, albeit weakly, reflect the clinical severity of CMT. In the future, NfL may be used, either individually or collaboratively, as a biomarker in the clinical context of suspected CMT; however, several issues need to be addressed first