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6 results on '"Hoskins, B.E."'

1. A systematic approach to mapping recessive disease genes in individuals from outbred populations

Author

Hildebrandt, F., Heeringa, S.F., Rueschendorf, F., Attanasio, M., Nuernberg, G., Becker, C., Seelow, D., Huebner, N., Chernin, G., Vlangos, C.N., Zhou, W., O'Toole, J.F., Hoskins, B.E., Wolf, M.T., Hinkes, B.G., Chaib, H., Ashraf, S., Allen, S.J., Vega-Warner, V., Wise, E., Harville, H.M., Lyons, R.H., Washburn, J., Macdonald, J., Nuernberg, P., and Otto, E.A.

Subjects
Cardiovascular and Metabolic Diseases
Abstract

The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes.

Published
2009

3. Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.

Author

O'Toole, J.F., Liu, Y., Davis, E.E., Westlake, C.J., Attanasio, M., Otto, E.A., Seelow, D., Nurnberg, G., Becker, C., Nuutinen, M., Karppa, M., Ignatius, J., Uusimaa, J., Pakanen, S., Jaakkola, E., Heuvel, L.P.W.J. van den, Fehrenbach, H., Wiggins, R., Goyal, M., Zhou, W., Wolf, M.T., Wise, E., Helou, J., Allen, S.J., Murga-Zamalloa, C.A., Ashraf, S., Chaki, M., Heeringa, S., Chernin, G., Hoskins, B.E., Chaib, H., Gleeson, J., Kusakabe, T., Suzuki, T., Isaac, R.E., Quarmby, L.M., Tennant, B., Fujioka, H., Tuominen, H., Hassinen, I., Lohi, H., Houten, J.L. van, Rotig, A., Sayer, J.A., Rolinski, B., Freisinger, P., Madhavan, S.M., Herzer, M., Madignier, F., Prokisch, H., Nurnberg, P., Jackson, P.K., Khanna, H., Katsanis, N., Hildebrandt, F., O'Toole, J.F., Liu, Y., Davis, E.E., Westlake, C.J., Attanasio, M., Otto, E.A., Seelow, D., Nurnberg, G., Becker, C., Nuutinen, M., Karppa, M., Ignatius, J., Uusimaa, J., Pakanen, S., Jaakkola, E., Heuvel, L.P.W.J. van den, Fehrenbach, H., Wiggins, R., Goyal, M., Zhou, W., Wolf, M.T., Wise, E., Helou, J., Allen, S.J., Murga-Zamalloa, C.A., Ashraf, S., Chaki, M., Heeringa, S., Chernin, G., Hoskins, B.E., Chaib, H., Gleeson, J., Kusakabe, T., Suzuki, T., Isaac, R.E., Quarmby, L.M., Tennant, B., Fujioka, H., Tuominen, H., Hassinen, I., Lohi, H., Houten, J.L. van, Rotig, A., Sayer, J.A., Rolinski, B., Freisinger, P., Madhavan, S.M., Herzer, M., Madignier, F., Prokisch, H., Nurnberg, P., Jackson, P.K., Khanna, H., Katsanis, N., and Hildebrandt, F.

Abstract

Contains fulltext : 88043.pdf (publisher's version ) (Closed access), The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.

Published
2010

4. Genetic predictors of cardiovascular morbidity in Bardet-Biedl syndrome.

Author

Forsythe, E., Sparks, K., Hoskins, B.E., Bagkeris, E., McGowan, B.M., Carroll, P.V., Huda, M.S.B., Mujahid, S., Peters, C., Barrett, T., Mohammed, S., and Beales, P.L.

Subjects
LAURENCE-Moon-Biedl syndrome, CARDIOVASCULAR diseases, DYSTROPHY, RETINAL degeneration, OBESITY, GENETIC mutation
Abstract

Bardet-Biedl syndrome is a rare ciliopathy characterized by retinal dystrophy, obesity, intellectual disability, polydactyly, hypogonadism and renal impairment. Patients are at high risk of cardiovascular disease. Mutations in BBS1 and BBS10 account for more than half of those with molecular confirmation of the diagnosis. To elucidate genotype-phenotype correlations with respect to cardiovascular risk indicators 50 patients with mutations in BBS1 were compared with 19 patients harbouring BBS10 mutations. All patients had truncating, missense or compound missense/truncating mutations. The effect of genotype and mutation type was analysed. C-reactive protein was higher in those with mutations in BBS10 and homozygous truncating mutations (p = 0.013 and p = 0.002, respectively). Patients with mutations in BBS10 had higher levels of C peptide than those with mutations in BBS1 (p = 0.043). Triglyceride levels were significantly elevated in patients with homozygous truncating mutations (p = 0.048). Gamma glutamyl transferase was higher in patients with homozygous truncating mutations (p = 0.007) and heterozygous missense and truncating mutations (p = 0.002) than those with homozygous missense mutations. The results are compared with clinical cardiovascular risk factors. Patients with missense mutations in BBS1 have lower biochemical cardiovascular disease markers compared with patients with BBS10 and other BBS1 mutations. This could contribute to stratification of the clinical service. [ABSTRACT FROM AUTHOR]

Published
2015
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5. Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders

Author

Hasselbacher, K., primary, Wiggins, R.C., additional, Matejas, V., additional, Hinkes, B.G., additional, Mucha, B., additional, Hoskins, B.E., additional, Ozaltin, F., additional, Nürnberg, G., additional, Becker, C., additional, Hangan, D., additional, Pohl, M., additional, Kuwertz-Bröking, E., additional, Griebel, M., additional, Schumacher, V., additional, Royer-Pokora, B., additional, Bakkaloglu, A., additional, Nürnberg, P., additional, Zenker, M., additional, and Hildebrandt, F., additional

Published
2006
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6. Bridging the gap between monogenic and multifactorial disease: the Bardet-Biedl syndrome.

Author

Beales, Philip, Ansley, S.J., Hoskins, B.E., Badano, J.L., Ross, A., Eichers, E.R., Hill, J., Lewis, R.A., Scambler, P.J., Davidson, W.S., Katsanis, N., and Lupski, J.R.

Subjects
LAURENCE-Moon-Biedl syndrome, MONOGENIC functions, ALTERNATING generations, GENETIC disorders
Abstract

Our traditional view of inheritance separates monogenic diseases from multifactorial traits by virtue of their complexity and mechanism of inheritance. Bardet-Biedl syndrome (BBS) is a genetically and clinically heterogeneous disorder in which the overwhelming evidence is in favour of an autosomal recessive mode of inheritance. BBS is caused by mutations in at least seven loci (BBS1-7), five of which are now cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci is necessary for pathogenesis. To date, all of the five known BBS loci have been implicated in this mode of oligogenic disease transmission. This talk will focus on the initial evidence that has led us to formulate the hypothesis of "triallelic inheritance", however, recent data implicating BBS1, in mutational terms the greatest contributor to the syndrome, will also be discussed. Finally, examples in which a third allele may exert an effect on the severity of disease will be presented. These data have led us to re-evaluate the manner in which we regard monogenic and polygenic disease and postulate that similar genetic interactions may underlie common disease pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2003

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