21 research outputs found

    Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay

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    Background: Loss-of-function mutations in CDKN1C cause overgrowth, that is, Beckwith-Wiedemann syndrome (BWS), while gain-of-function variants in the gene’s PCNA binding motif cause a growth-restricted condition called IMAGe syndrome. We report on a boy with a remarkable mixture of both syndromes, with developmental delay and microcephaly as additional features. Methods: Whole-exome DNA sequencing and ultra-deep RNA sequencing of leucocyte-derived and fibroblast-derived mRNA were performed in the family. Results: We found a maternally inherited variant in the IMAGe hotspot region: NM_000076.2(CDKN1C) c.822_826delinsGAGCTG. The asymptomatic mother had inherited this variant from her mosaic father with mild BWS features. This delins caused tissue-specific frameshifting resulting in at least three novel mRNA transcripts in the boy. First, a splice product causing CDKN1C truncation was the likely cause of BWS. Second, an alternative splice product in fibroblasts encoded IMAGe-associated amino acid substitutions. Third, we speculate that developmental delay is caused by a change in the alternative CDKN1C-201 (ENST00000380725.1) transcript, encoding a novel isoform we call D (UniProtKB: A6NK88). Isoform D is distinguished from isoforms A and B by alternative splicing within exon 1 that changes the reading frame of the last coding exon. Remarkably, this delins changed the reading frame back to the isoform A/B type, resulting in a hybrid D–A/B isoform. Conclusion: Three different cell-type-dependent RNA products can explain the co-occurrence of both BWS and IMAGe features in the boy. Possibly, brain expression of hybrid isoform D–A/B is the cause of developmental delay and microcephaly, a phenotypic feature not previously reported in CDKN1C patients.publishedVersio

    Assessing the reproductive biology of the Greenland shark (Somniosus microcephalus)

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    The Greenland shark (Somniosus microcephalus, Squaliformes: Somniosidae) is a long-lived Arctic top predator, which in combination with the high historical and modern fishing pressures, has made it subject to increased scientific focus in recent years. Key aspects of reproduction are not well known as exemplified by sparse and contradictory information e.g. on birth size and number of pups per pregnancy. This study represents the first comprehensive work on Greenland shark reproductive biology based on data from 312 specimens collected over the past 60 years. We provide guidelines quantifying reproductive parameters to assess specific maturation stages, as well as calculate body length-at-maturity (TL50) which was 2.84±0.06 m for males and 4.19±0.04 m for females. From the available information on the ovarian fecundity of Greenland sharks as well as a meta-analysis of Squaliform reproductive parameters, we estimate up to 200–324 pups per pregnancy (depending on maternal size) with a body length-at-birth of 35–45 cm. These estimates remain to be verified by future observations from gravid Greenland sharks

    Genetic relationships among species of Contracaecum railliet & Henry, 1912 and Phocascaris Höst, 1932 (Nematoda: Anisakidae) from pinnipeds inferred from mitochondrial cox2 sequences, and congruence with allozyme data

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    The genetic relationships among 11 taxa, belonging to the genus Contracaecum (C. osculatum A, C. osculatum B, C. osculatum (s.s.), C. osculatum D, C. osculatum E, C. osculatum baicalensis, C. mirounga, C. radiatum, C. ogmorhini (s.s.), C. margolisi) and Phocascaris IPhocascaris cystophorae), parasites as adults of seals, were inferred from sequence analysis (519 bp) of the mitochbndrial cytochrome c oxidase subunit II (mtDNA cox2) gene. Phylogenetic analyses obtained from Parsimony (MP) and Neighbour-Joining (NJ) K2P distance values generated similar topologies, each well supported at major nodes. All analyses delineated two main clades: the first encompassing the parasites of the phocid seals, i.e. the C. osculatum species complex, C. osculatum baicalensis, C. mirounga and C. radiatum, with the latter two species forming a separate subclade; the second including the parasites of otarids, i.e. C. ogmorhini (s.s.) and C. margolisi. An overall high congruence between mtDNA inferred tree topologies and those produced from nuclear data sets (20 allozyme loci) was observed. Comparison of the phylogenetic hypothesis here produced for Contracaecum spp. plus Phocascaris with those currently available for their definitive hosts (pinnipeds) suggests parallelism between hosts and parasite phylogenetic tree topologies.Fil: Mattiucci, Simonetta. Università di Roma; ItaliaFil: Paoletti, M.. Università di Roma; Italia. Università degli Studi della Tuscia; ItaliaFil: Webb, S.C.. Cawthron Institute; Nueva ZelandaFil: Sardella, Norma Haydee. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología. Laboratorio de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Timi, Juan Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Berland, B.. University of Bergen; NoruegaFil: Nascetti, G.. Università degli Studi della Tuscia; Itali

    Double paternal uniparental isodisomy 7 and 15 presenting with Beckwith–Wiedemann spectrum features

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    Here we describe for the first time double paternal uniparental isodisomy (iUPD) 7 and 15 in a baby boy with features in the Beckwith–Wiedemann syndrome spectrum (BWSp) (placentomegaly, hyperinsulinism, enlarged viscera, hemangiomas, and earlobe creases) in addition to conjugated hyperbilirubinemia. His phenotype was also reminiscent of genome-wide paternal uniparental isodisomy. We discuss the most likely origin of the UPDs: a maternal double monosomy 7 and 15 rescued by duplication of the paternal chromosomes after fertilization. So far, paternal UPD7 is not associated with an abnormal phenotype, whereas paternal UPD15 causes Angelman syndrome. Methylation analysis for other clinically relevant imprinting disorders, including BWSp, was normal. Therefore, we hypothesized that the double UPD affected other imprinted genes. To look for such effects, patient fibroblast RNA was isolated and analyzed for differential expression compared to six controls. We did not find apparent transcription differences in imprinted genes outside Chromosomes 7 and 15 in patient fibroblast. PEG10 (7q21.3) was the only paternally imprinted gene on these chromosomes up-regulated beyond double-dose expectation (sixfold). We speculate that a high PEG10 level could have a growth-promoting effect as his phenotype was not related to aberrations in BWS locus on 11p15.5 after DNA, RNA, and methylation testing. However, many genes in gene sets associated with growth were up-regulated. This case broadens the phenotypic spectrum of UPDs but does not show evidence of involvement of an imprinted gene network.publishedVersio

    LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions

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    LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%–26% lower than expected from Hardy–Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism.publishedVersio

    Musings on nematode parasites

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    Devonia perrieri (Malard, 1903) (Bivalvia) found in situ on the holothurian Leptosynapta inhaerens (Müller, 1776) in Norway

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    The ectosymbiotic bivalve, Devonia perrieri, has earlier been found non-associated with its host in grab samples in Western Norway, but has never been found on its purported host, Leptosynapta inhaerens. Here we show it for the first time on its host, Leptosynapta inhaerens, in Norwegian waters. This confirms that the host in Western Norway is same as elsewhere in the bivalve’s distribution area

    Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay

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    Background: Loss-of-function mutations in CDKN1C cause overgrowth, that is, Beckwith-Wiedemann syndrome (BWS), while gain-of-function variants in the gene’s PCNA binding motif cause a growth-restricted condition called IMAGe syndrome. We report on a boy with a remarkable mixture of both syndromes, with developmental delay and microcephaly as additional features. Methods: Whole-exome DNA sequencing and ultra-deep RNA sequencing of leucocyte-derived and fibroblast-derived mRNA were performed in the family. Results: We found a maternally inherited variant in the IMAGe hotspot region: NM_000076.2(CDKN1C) c.822_826delinsGAGCTG. The asymptomatic mother had inherited this variant from her mosaic father with mild BWS features. This delins caused tissue-specific frameshifting resulting in at least three novel mRNA transcripts in the boy. First, a splice product causing CDKN1C truncation was the likely cause of BWS. Second, an alternative splice product in fibroblasts encoded IMAGe-associated amino acid substitutions. Third, we speculate that developmental delay is caused by a change in the alternative CDKN1C-201 (ENST00000380725.1) transcript, encoding a novel isoform we call D (UniProtKB: A6NK88). Isoform D is distinguished from isoforms A and B by alternative splicing within exon 1 that changes the reading frame of the last coding exon. Remarkably, this delins changed the reading frame back to the isoform A/B type, resulting in a hybrid D–A/B isoform. Conclusion: Three different cell-type-dependent RNA products can explain the co-occurrence of both BWS and IMAGe features in the boy. Possibly, brain expression of hybrid isoform D–A/B is the cause of developmental delay and microcephaly, a phenotypic feature not previously reported in CDKN1C patients

    Skjøtselsråd for dragehode (Dracocephalum ruyschiana)

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    Har du sett den særegne og vakre planten dragehode noen gang? Kanskje er du en av de heldige som har opplevd de dypblå blomstene på et av denne plantens få voksesteder? Dragehode er nemlig en meget sjelden plante i Norge. Derfor har den status som prioritert art etter Naturmangfoldloven og er dessverre også på den norske rødlista for sjeldne og truete arter.publishedVersio
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