Crowe A et al. (2018) Infect Genet Evol "PCR-coupled sequencing achieves specific diagnosis of onchocerciasis in a challenging clinical case, to underpin effective treatment and clinical management."

Crowe A, Koehler AV, Gasser RB, Sheorey H, Tolpinrud A

[Infect Genet Evol, 2018]

This study demonstrates the utility of a PCR-based DNA sequencing approach to make a specific diagnosis of onchocerciasis in a returned traveller. Although a clinical diagnosis was not possible, the surgical excision of a suprascapular nodule from this patient, combined with an histological examination of this nodule and PCR-based sequencing of DNA from a nematode from this lesion solved the case. The analysis of DNA sequence data confirmed the presence of Onchocerca volvulus infection, supporting an effective treatment-clinical management strategy for the patient.

Barua P et al. (2011) Southeast Asian J Trop Med Public Health "A rare case of ocular onchocerciasis in India."

Bhuyan S, Alam ST, Hazarika NK, Barua P, Barua N, Sharma A

[Southeast Asian J Trop Med Public Health, 2011]

Onchocerca volvulus is a spirurid nematode that mainly affects the rural poor of Sub-Saharan Africa, Yemen and parts of Central and South Africa. River blindness, caused by Onchocerca volvulus, is considered to be the second commonest infectious cause of blindness worldwide. We report a rare case of ocular onchocerciasis where a live adult worm was extracted from the eye of a patient from a nonendemic region. The worm was identified as Onchocerca volvulus based on morphological features. The patient was treated with Ivermectin (0.2 mg/kg). At six months follow-up she had complete remission of symptoms.

Sorkac A et al. (2016) PLoS One "In Vivo Modelling of ATP1A3 G316S-Induced Ataxia in C. elegans Using CRISPR/Cas9-Mediated Homologous Recombination Reveals Dominant Loss of Function Defects."

Alcantara IC, Hart AC, Sorkac A

[PLoS One, 2016]

The NIH Undiagnosed Diseases Program admitted a male patient with unclassifiable late-onset ataxia-like symptoms. Exome sequencing revealed a heterozygous de novo mutation converting glycine 316 to serine in ATP1A3, which might cause disease. ATP1A3 encodes the Na+/K+ ATPase pump 3-subunit. Using CRISPR/Cas9-mediated homologous recombination for genome editing, we modelled this putative disease-causing allele in Caenorhabditis elegans, recreating the patient amino acid change in eat-6, the orthologue of ATP1A3. The impact of the mutation on eat-6 function at the neuromuscular junction was examined using two behavioural assays: rate of pharyngeal pumping and sensitivity to aldicarb, a drug that causes paralysis over time via the inhibition of acetylcholinesterase. The patient allele decreased pumping rates and caused hypersensitivity to aldicarb. Animals heterozygous for the allele exhibited similar defects, whereas loss of function mutations in eat-6 were recessive. These results indicate that the mutation is dominant and impairs the neuromuscular function. Thus, we conclude that the de novo G316S mutation in ATP1A3 likely causes or contributes to patient symptoms. More broadly, we conclude that, for conserved genes, it is possible to rapidly and easily model human diseases in C. elegans using CRIPSR/Cas9 genome editing.

Bartlett A et al. (1975) Tropenmed Parasitol "Preliminary studies on the application of enzyme immunoassay in the detection of antibodies in onchocerciasis."

Bidwell DE, Bartlett A, Voller A

[Tropenmed Parasitol, 1975]

Preliminary enzyme-linked immunosorbent assay (ELISA) with serum from a patient with onchoceriasis revealed extensive cross-reactions with various nematode antigens. Further tests on a batch of sera from people with proven O. volvulus infections using O. gutturosa antigen, showed that almost all the sera gave higher ELISA values than did control African sera.

Foulquier F et al. (2006) Proc Natl Acad Sci U S A "Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II."

Mills P, Winchester B, Jaeken J, Vasile E, Schollen E, Matthijs G, Foulquier F, Krieger M, Annaert W, Quelhas D, Raemaekers T, Callewaert N

[Proc Natl Acad Sci U S A, 2006]

The conserved oligomeric Golgi (COG) complex is a heterooctameric complex that regulates intraGolgi trafficking and the integrity of the Golgi compartment in eukaryotic cells. Here, we describe a patient with a mild form of congenital disorder of glycosylation type II (CDG-II) that is caused by a deficiency in the Cog1 subunit of the complex. This patient has a defect in both N- and O-glycosylation. Mass spectrometric analysis of the structures of the N-linked glycans released from glycoproteins from the patient''s serum revealed a reduction in sialic acid and galactose residues. Peanut agglutinin (PNA) lectin staining revealed a decrease in sialic acids on core 1 mucin type O-glycans, indicating a combined defect in N- and O-glycosylation. Sequence analysis of the COG1 cDNA and gene identified a homozygous insertion of a single nucleotide (2659-2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids. This mutation destabilizes several other COG subunits and alters their subcellular localization and hence the overall integrity of the COG complex. This results in reduced levels and/or altered Golgi localization of alpha-mannosidase II and beta-1,4 galactosyltransferase I, which links it to the glycosylation deficiency. Transfection of primary fibroblasts of this patient with the full length hemagglutinin-tagged Cog1 indeed restored beta-1,4 galactosyltransferase Golgi localization. We propose naming this disorder CDG-II/Cog1, or CDG-II caused by Cog1 deficiency.

Binzak BA et al. (2001) Am J Hum Genet "Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency."

Poggi-Bach J, Lee YM, Wevers RA, Vockley J, Binzak BA, Hwu WL, Hoard HM, Moolenaar SH, Engelke UF, Vockley JG

[Am J Hum Genet, 2001]

Dimethylglycine dehydrogenase (DMGDH) (E.C. number 1.5.99.2) is a mitochondrial matrix enzyme involved in the metabolism of choline, converting dimethylglycine to sarcosine. Sarcosine is then transformed to glycine by sarcosine dehydrogenase (E.C. number 1.5.99.1). Both enzymes use flavin adenine dinucleotide and folate in their reaction mechanisms. We have identified a 38-year-old man who has a lifelong condition of fishlike body odor and chronic muscle fatigue, accompanied by elevated levels of the muscle form of creatine kinase in serum. Biochemical analysis of the patient''s serum and urine, using (1)H-nuclear magnetic resonance NMR spectroscopy, revealed that his levels of dimethylglycine were much higher than control values. The cDNA and the genomic DNA for human DMGDH (hDMGDH) were then cloned, and a homozygous A-->G substitution (326 A-->G) was identified in both the cDNA and genomic DNA of the patient. This mutation changes a His to an Arg (H109R). Expression analysis of the mutant cDNA indicates that this mutation inactivates the enzyme. We therefore confirm that the patient described here represents the first reported case of a new inborn error of metabolism, DMGDH deficiency.

Galindo-Malagn XA et al. (2022) Zootaxa "New species, synonymies and records in the genus Rhagovelia Mayr, 1865 (Hemiptera: Heteroptera: Veliidae) from Colombia."

Moreira FFF, Morales I, Mondragn-F SP, Galindo-Malagn XA

[Zootaxa, 2022]

Rhagovelia medinae sp. nov., of the hambletoni group (angustipes complex), and R. utria sp. nov., of the hirtipes group (robusta complex), are described, illustrated, and compared with similar congeners. Based on the examination of type specimens, six new synonymies are proposed: R. elegans Uhler, 1894 = R. pediformis Padilla-Gil, 2010, syn. nov.; R. cauca Polhemus, 1997 = R. azulita Padilla-Gil, 2009, syn. nov., R. huila Padilla-Gil, 2009, syn. nov., R. oporapa Padilla-Gil, 2009, syn. nov, R. quilichaensis Padilla-Gil, 2011, syn. nov.; and R. gaigei, Drake Hussey, 1947 = R. victoria Padilla-Gil, 2012 syn. nov. The first record from Colombia is presented for R. trailii (White, 1879), and the distributions of the following species are extended in the country: R. cali Polhemus, 1997, R. castanea Gould, 1931, R. cauca Polhemus, 1997, R. gaigei Drake Hussey, 1957, R. elegans Uhler, 1894, R. femoralis Champion, 1898, R. malkini Polhemus, 1997, R. perija Polhemus, 1997, R. sinuata Gould, 1931, R. venezuelana Polhemus, 1997, R. williamsi Gould, 1931, and R. zeteki Drake, 1953.

Austin KM et al. (2005) Blood "The Shwachman-Diamond SBDS protein localizes to the nucleolus."

Shimamura A, Austin KM, Leary RJ

[Blood, 2005]

Shwachman-Diamond syndrome (SDS) is an autosomal recessively inherited disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. The gene for this syndrome, SBDS, encodes a highly conserved novel protein. We characterized Shwachman-Bodian-Diamond syndrome (SBDS) protein expression and intracellular localization in 7 patients with SDS and healthy controls. As predicted by gene mutation, 4 patients with SDS exhibited no detectable full-length SBDS protein. Patient DF277, who was homozygous for the IVS2 + 2 T>C splice donor mutation, expressed scant levels of SBDS protein. Patient SD101 expressed low levels of SBDS protein harboring an R169C missense mutation. Patient DF269, who carried no detectable gene mutations, expressed wild-type levels of SBDS protein to add further support to the growing body of evidence for additional gene(s) that might contribute to the pathogenesis of the disease phenotype. The SBDS protein was detected in both the nucleus and the cytoplasm of normal control fibroblasts, but was particularly concentrated within the nucleolus. SBDS localization was cell-cycle dependent, with nucleolar localization during G1 and G2 and diffuse nuclear localization during S phase. SBDS nucleolar localization was intact in SD101 and DF269. The intranucleolar localization of SBDS provides further supportive evidence for its postulated role in rRNA processing.

Carter ME et al. (2010) J Infect Dis "A subtype of a Pseudomonas aeruginosa cystic fibrosis epidemic strain exhibits enhanced virulence in a murine model of acute respiratory infection."

Winstanley C, Kadioglu A, Fothergill JL, Rajakumar K, Carter ME, Walshaw MJ

[J Infect Dis, 2010]

BACKGROUND: The Liverpool epidemic strain (LES) of Pseudomonas aeruginosa is a particularly successful cystic fibrosis (CF) pathogen associated with transmissibility, increased patient morbidity, and, unusually, infection of the non-CF parents of a patient with CF. METHODS: Using assays for virulence-associated exoproducts, biofilm formation, Caenorhabditis elegans killing, and a murine model of acute respiratory infection, we compared the pathogenic behavior of representatives of 4 subtypes of the LES, including LES431, an isolate associated with the infection of a parent without CF. RESULTS: The quorum-sensing-defective lasR mutant LES400 produced less exoproduct and had less C. elegans killing activity than the other LES subtypes, which were represented by LES431, LESB58, and LESB65. LES431 was deficient in biofilm formation, compared with the other LES sub-types. The LES subtypes displayed a range of virulence in the mouse model, with LES431 being by far the most virulent. The genome-sequenced isolate LESB58, effective at establishing infections in a rat model of chronic infection, was the least virulent subtype in the murine acute infection model. CONCLUSIONS: LES isolates display widely variable pathogenic characteristics. LES431, associated with transmission to the non-CF parent of a CF patient, represents a "hypervirulent" subtype more adapted to acute infections than chronic infections.

Luhn K et al. (2001) Nat Genet "The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter."

Eckhardt M, Gerardy-Schahn R, Luhn K, Wild MK, Vestweber D

[Nat Genet, 2001]

Leukocyte adhesion deficiency II(LAD II) is characterized by the lack of fucosylated glycoconjugates, including selectin ligands, causing immunodeficiency and severe mental and growth retardation(1-3) No deficiency in fucosyltransferase activities(2,4) or in the activities of enzymes involved in GDP-fucose biosynthesis(5) has been found. Instead, the transport of GDP-fucose into isolated Golgi vesicles of LAD II cells appeared to be reduced(6). To identify the gene mutated in LAD II, we cloned 12 cDNAs from Caenorhabditis elegans, encoding multi-spanning transmembrane proteins with homology to known nucleotide sugar transporters, and transfected them into fibroblasts from an LAD II patient. One of these clones re-established expression of fucosylated glycoconjugates with high efficiency and allowed us to identify a human homolog with 55% identity, which also directed re-expression of fucosylated glycoconjugates, Both proteins were localized to the Golgi, The corresponding endogenous protein in LAD II cells had an R147C amino acid change in the conserved fourth transmembrane region. Overexpression of this mutant protein in cells from a patient with LAD did not rescue fucosylation, demonstrating that the point mutation affected the activity of the protein. Thus, we have identified the first putative CDP fucose transporter, which has been highly conserved throughout evolution. A point mutation in its gene is responsible for the disease in this patient with LAD II.