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Utilization of automated cilia analysis to characterize novel INPP5E variants in patients with non-syndromic retinitis pigmentosa.
Whiting, Kae R; Haer-Wigman, Lonneke; Florijn, Ralph J; van Beek, Ronald; Oud, Machteld M; Plomp, Astrid S; Boon, Camiel J F; Kroes, Hester Y; Roepman, Ronald.
Afiliación
  • Whiting KR; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Haer-Wigman L; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Florijn RJ; Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • van Beek R; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Oud MM; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Plomp AS; Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • Boon CJF; Department of Ophthalmology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • Kroes HY; Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
  • Roepman R; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Eur J Hum Genet ; 2024 May 28.
Article en En | MEDLINE | ID: mdl-38806661
ABSTRACT
INPP5E encodes inositol polyphosphate-5-phosphatase E, an enzyme involved in regulating the phosphatidylinositol (PIP) makeup of the primary cilium membrane. Pathogenic variants in INPP5E hence cause a variety of ciliopathies genetic disorders caused by dysfunctional cilia. While the majority of these disorders are syndromic, such as the neuronal ciliopathy Joubert syndrome, in some cases patients will present with an isolated phenotype-most commonly non-syndromic retinitis pigmentosa (RP). Here, we report two novel variants in INPP5E identified in two patients with non-syndromic RP patient 1 with compound heterozygous variants (c.1516C > T, p.(Q506*), and c.847G > A, p.(A283T)) and patient 2 with a homozygous variant (c.1073C > T, p.(P358L)). To determine whether these variants were causative for the phenotype in the patients, automated ciliary phenotyping of patient-derived dermal fibroblasts was performed for percent ciliation, cilium length, retrograde IFT trafficking, and INPP5E localization. In both patients, a decrease in ciliary length and loss of INPP5E localization in the primary cilia were seen. With these molecular findings, we can confirm functionally that the novel variants in INPP5E are causative for the RP phenotypes seen in both patients. Additionally, this study demonstrates the usefulness of utilizing ciliary phenotyping as an assistant in ciliopathy diagnosis and phenotyping.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Eur J Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Eur J Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido