CAV3 mutation in a patient with transient hyperCKemia and myalgia

Mutations in caveolin-3 (CAV3) can lead to different clinical phenotypes affecting skeletal or cardiac muscles. Here, we describe a patient with Klinefelter syndrome, ulcerative colitis and Sjögren syndrome, who developed transient hyperCKemia, myalgia and mild muscular weakness. Using whole exome sequencing (WES), a missense mutation G169A was found in the CAV3 gene. In addition, we identified a homozygous frameshift deletion in MS4A12 that may contribute to inflammatory bowel disease, further demonstrating usefulness of WES in dual molecular diagnoses

Novel parent-of-origin-specific differentially methylated loci on chromosome 16

BACKGROUND: Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. RESULTS: To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. CONCLUSIONS: Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Evolutionarily recent, insertional fission of mitochondrial cox2 into complementary genes in bilaterian Metazoa

Abstract Background Mitochondrial genomes (mtDNA) of multicellular animals (Metazoa) with bilateral symmetry (Bilateria) are compact and usually carry 13 protein-coding genes for subunits of three respiratory complexes and ATP synthase. However, occasionally reported exceptions to this typical mtDNA organization prompted speculation that, as in protists and plants, some bilaterian mitogenomes may continue to lose their canonical genes, or may even acquire new genes. To shed more light on this phenomenon, a PCR-based screen was conducted to assess fast-evolving mtDNAs of apocritan Hymenoptera (Arthropoda, Insecta) for genomic rearrangements that might be associated with the modification of mitochondrial gene content. Results Sequencing of segmental inversions, identified in the screen, revealed that the cytochrome oxidase subunit II gene (cox2) of Campsomeris (Dielis) (Scoliidae) was split into two genes coding for COXIIA and COXIIB. The COXII-derived complementary polypeptides apparently form a heterodimer, have reduced hydrophobicity compared with the majority of mitogenome-encoded COX subunits, and one of them, COXIIB, features increased content of Cys residues. Analogous cox2 fragmentation is known only in two clades of protists (chlorophycean algae and alveolates), where it has been associated with piecewise relocation of this gene into the nucleus. In Campsomeris mtDNA, cox2a and cox2b loci are separated by a 3-kb large cluster of several antiparallel overlapping ORFs, one of which, qnu, seems to encode a nuclease that may have played a role in cox2 fission. Conclusions Although discontinuous mitochondrial protein genes encoding fragmented, complementary polypeptides are known in protists and some plants, split cox2 of Campsomeris is the first case of such a gene arrangement found in animals. The reported data also indicate that bilaterian animal mitogenomes may be carrying lineage-specific genes more often than previously thought, and suggest a homing endonuclease-based mechanism for insertional mitochondrial gene fission

Intercompartmental Piecewise Gene Transfer

Gene relocation from the residual genomes of organelles to the nuclear genome still continues, although as a scaled down evolutionary phenomenon, limited in occurrence mostly to protists (sensu lato) and land plants. During this process, the structural integrity of transferred genes is usually preserved. However, the relocation of mitochondrial genes that code for respiratory chain and ribosomal proteins is sometimes associated with their fragmentation into two complementary genes. Herein, this review compiles cases of piecewise gene transfer from the mitochondria to the nucleus, and discusses hypothesized mechanistic links between the fission and relocation of those genes

New Dielis species and structural dichotomy of the mitochondrial cox2 gene in Scoliidae wasps

Abstract Some mitochondrial protein-coding genes of protists and land plants have split over the course of evolution into complementary genes whose products can form heteromeric complexes that likely substitute for the undivided proteins. One of these genes, cox2, has also been found to have split in animals, specifically in Scoliidae wasps (Hymenoptera: Apocrita) of the genus Dielis (Campsomerini), while maintaining the conventional structure in related Scolia (Scoliini). Here, a hitherto unrecognized Nearctic species of Dielis, D. tejensis, is described based on its phenotype and mtDNA. The mitogenome of D. tejensis sp. nov. differs from that of the sympatric sibling species Dielis plumipes fossulana by the reduced size of the cox2-dividing insert, which, however, still constitutes the fifth part of the mtDNA; an enlarged nad2-trnW intergenic region; the presence of two trnK ttt paralogues; and other features. Both species of Dielis have a unique insertion of a threonine in COXIIA, predicted to be involved in COXIIA-COXIIB docking, and substitutions of two hydrophobic residues with redox-active cysteines around the CuA centre in COXIIB. Importantly, the analysis of mtDNA from another Campsomerini genus, Megacampsomeris, shows that its cox2 gene is also split. The presented data highlight evolutionary processes taking place in hymenopteran mitogenomes that do not fall within the mainstream of animal mitochondrion evolution

Somatic mosaicism in Maniola jurtina (Nymphalidae: Satyrinae)

Volume: 48Start Page: 264End Page: 26

New host plant and distributional records for some Eburia Lepeletier & Audinet-Serville (Coleoptera: Cerambycidae) in North America including Mexico

Volume: 78Start Page: 66End Page: 6

Additional file 1: Figure S1. of Evolutionarily recent, insertional fission of mitochondrial cox2 into complementary genes in bilaterian Metazoa

Schematic representation of a PCR-based screen for segmental inversions in mtDNA. Figure S2. Alignment of COXII sequences in the region corresponding to the C- and N-termini of Campsomeris COXIIA and COXIIB, respectively. Figure S3. C. p. fossulana cox2a gene. Figure S4. C. p. fossulana cox2b gene. Figure S5. Amino acid residue content in COXII of C. p. fossulana, S. bicincta, and A. mellifera. Figure S6. A + T content along the C. p. fossulana mtDNA. Figure S7. Comparison of QNU and WFW orthologous polypeptides from two Campsomeris species. Figure S8. In silico-determined nucleic acid-binding potential of the C. p. fossulana QNU polypeptide. Figure S9. Alignment of the Campsomeris mtDNA sequences around the cox2 split site. Table S1. Cys residue content of the COXII intermembrane space domain in canonical and modified COXII polypeptides. Table S2. Relative synonymous codon usage (RSCU) by mitochondrial genes/ORFs of C. p. fossulana. Table S3. Amino acid sequence similarities between C. p. fossulana polypeptide QNU and nucleic acid-interacting proteins. Table S4. Primers used for RT-qPCR. (PDF 1205 kb