A milder form of NSRP1-associated neurodevelopmental disorder, caused by a missense variant in the nuclear localization signal.

Autor: Neuens S; Department of Genetics, Hôpital Universitaire Des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium., Kausar M; School of Life Sciences, Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea., Kang SK; School of Life Sciences, Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea., Soblet J; Department of Genetics, Hôpital Universitaire Des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.; Center for Human Genetics, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.; Interuniversity Institute of Bioinformatics in Brussels (IB)2, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium., Van Dooren S; Interuniversity Institute of Bioinformatics in Brussels (IB)2, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium.; Interuniversity Genomics High Throughput Core (BRIGHTcore), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.; Vrije Universiteit Brussel (VUB), Clinical Sciences, Research Group Genetics, Reproduction and Development (GRAD), Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Jette, Belgium., Olsen C; Interuniversity Institute of Bioinformatics in Brussels (IB)2, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium.; Interuniversity Genomics High Throughput Core (BRIGHTcore), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.; Vrije Universiteit Brussel (VUB), Clinical Sciences, Research Group Genetics, Reproduction and Development (GRAD), Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Jette, Belgium., Janssen T; Interuniversity Genomics High Throughput Core (BRIGHTcore), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.; Vrije Universiteit Brussel (VUB), Clinical Sciences, Research Group Genetics, Reproduction and Development (GRAD), Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Jette, Belgium., Caljon B; Interuniversity Genomics High Throughput Core (BRIGHTcore), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.; Vrije Universiteit Brussel (VUB), Clinical Sciences, Research Group Genetics, Reproduction and Development (GRAD), Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Jette, Belgium., Jun CD; School of Life Sciences, Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea., Smits G; Department of Genetics, Hôpital Universitaire Des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.; Center for Human Genetics, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.; Interuniversity Institute of Bioinformatics in Brussels (IB)2, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium., Coppens S; Center for Human Genetics, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium., Vilain C; Department of Genetics, Hôpital Universitaire Des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.; Center for Human Genetics, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.; Interuniversity Institute of Bioinformatics in Brussels (IB)2, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2024 Oct; Vol. 194 (10), pp. e63727. Date of Electronic Publication: 2024 May 29.
DOI: 10.1002/ajmg.a.63727
Abstrakt: Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a splice factor found in nuclear speckles, which are small membrane-free organelles implicated in epigenetic regulation, chromatin organization, DNA repair, and RNA modification. Bi-allelic loss-of-function variants in NSRP1 have recently been identified in patients suffering from a severe neurodevelopmental disorder, presenting with neurodevelopmental delay, epilepsy, microcephaly, hypotonia, and spastic cerebral palsy. Described patients acquired neither independent walking nor speech and often showed anomalies on cerebral MRI. Here we describe the case of a 14-year-old girl with motor and language delay as well as intellectual disability, who presents an ataxic gait but walks without assistance and speaks in short sentences. Whole-genome sequencing revealed the compound heterozygous NSRP1 variants c.114 + 2T > G and c.1595T > A (p.Val532Glu). Functional validation using HEK293T cells transfected with either wild-type or mutated GFP-tagged Nsrp1 suggests that the Val532Glu variant interferes with the function of the nuclear localization signal, and leads to mislocalization of NSRP1 in the cytosol, thus confirming the pathogenicity of the observed variant. This case helps to expand the phenotypic and genetic spectrum associated with pathogenic NSRP1 variants and indicates that this diagnosis should also be suspected in patients with milder phenotypes.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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