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In vivo bioassay to test the pathogenicity of missense human AIP variants.
Aflorei, Elena Daniela; Klapholz, Benjamin; Chen, Chenghao; Radian, Serban; Dragu, Anca Neluta; Moderau, Nina; Prodromou, Chrisostomos; Ribeiro, Paulo S; Stanewsky, Ralf; Korbonits, Márta.
Afiliación
  • Aflorei ED; Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
  • Klapholz B; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • Chen C; Department of Cell and Developmental Biology, Division of Biosciences, Faculty of Life Sciences, University College London, London, UK.
  • Radian S; Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
  • Dragu AN; Department of Endocrinology, C.I. Parhon National Institute of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
  • Moderau N; Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
  • Prodromou C; Department of Cell and Developmental Biology, Division of Biosciences, Faculty of Life Sciences, University College London, London, UK.
  • Ribeiro PS; Protein Dynamics and Cell Signalling Laboratory, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • Stanewsky R; Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
  • Korbonits M; Protein Dynamics and Cell Signalling Laboratory, Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
J Med Genet ; 55(8): 522-529, 2018 08.
Article en En | MEDLINE | ID: mdl-29632148
BACKGROUND: Heterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to childhood-onset pituitary tumours. The pathogenicity of missense variants may pose difficulties for genetic counselling and family follow-up. OBJECTIVE: To develop an in vivo system to test the pathogenicity of human AIP mutations using the fruit fly Drosophila melanogaster. METHODS: We generated a null mutant of the Drosophila AIP orthologue, CG1847, a gene located on the Xchromosome, which displayed lethality at larval stage in hemizygous knockout male mutants (CG1847exon1_3 ). We tested human missense variants of 'unknown significance', with 'pathogenic' variants as positive control. RESULTS: We found that human AIP can functionally substitute for CG1847, as heterologous overexpression of human AIP rescued male CG1847exon1_3 lethality, while a truncated version of AIP did not restore viability. Flies harbouring patient-specific missense AIP variants (p.C238Y, p.I13N, p.W73R and p.G272D) failed to rescue CG1847exon1_3 mutants, while seven variants (p.R16H, p.Q164R, p.E293V, p.A299V, p.R304Q, p.R314W and p.R325Q) showed rescue, supporting a non-pathogenic role for these latter variants corresponding to prevalence and clinical data. CONCLUSION: Our in vivo model represents a valuable tool to characterise putative disease-causing human AIP variants and assist the genetic counselling and management of families carrying AIP variants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Mutación Missense / Péptidos y Proteínas de Señalización Intracelular / Estudios de Asociación Genética Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Med Genet Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Predisposición Genética a la Enfermedad / Mutación Missense / Péptidos y Proteínas de Señalización Intracelular / Estudios de Asociación Genética Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: J Med Genet Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido