Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder
Number of Authors: 612025 (English)In: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 27, no 2, article id 101278Article in journal (Refereed) Published
Abstract [en]
Purpose: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations.
Methods: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.
Results: We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a−/− mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition.
Conclusion: Our studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.
Place, publisher, year, edition, pages
Elsevier, 2025. Vol. 27, no 2, article id 101278
Keywords [en]
Endocytosis, INPP4A, Neurodevelopmental disorder, Phosphoinositide phosphatase, Translation reinitiation, adolescent, adult, amino terminal sequence, Article, biological model, brain size, cell migration, cerebellum disease, cerebellum hypoplasia, child, clinical article, clinical assessment, computer model, contracture, developmental delay, disease severity, exon, female, fibroblast, gene, genetic analysis, genetic variability, genotype phenotype correlation, human, infant, INPP4A gene, intellectual impairment, limb weakness, male, mental disease, microcephaly, molecular genetics, protein function, refractory epilepsy, short stature, visual impairment
National Category
Medical Genetics and Genomics Neurology Medical Biotechnology (Focus on Cell Biology, (incl. Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-24847DOI: 10.1016/j.gim.2024.101278ISI: 001414223700001PubMedID: 39315527Scopus ID: 2-s2.0-85214346640OAI: oai:DiVA.org:his-24847DiVA, id: diva2:1929225
Funder
Wellcome trust, 209083/Z/17/ZWellcome trust, 221951/Z/20/ZWellcome trust, 226083/Z/22/ZGerman Research Foundation (DFG), EXC-2049-390688087German Research Foundation (DFG), 2138/7-1 grant 469177153EU, FP7, Seventh Framework Programme, 608473
Note
CC BY 4.0
© 2024 The Authors
Correspondence Address: L.E. Rawlins; NIHR Academic Clinical Lecturer, Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Research, Innovation, Learning and Development Building, Royal Devon and Exeter Hospital, Exeter, Barrack Road, EX2 5DW, United Kingdom; email: l.rawlins@exeter.ac.uk; E.L. Baple; Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Research, Innovation, Learning and Development Building, Royal Devon and Exeter Hospital, Exeter, Barrack Road, EX2 5DW, United Kingdom; email: e.baple@exeter.ac.uk; A.H. Crosby; Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Research, Innovation, Learning and Development Building, Royal Devon and Exeter Hospital, Exeter, Barrack Road, EX2 5DW, United Kingdom; email: a.h.crosby@exeter.ac.uk; CODEN: GEMEF
This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre and University College London Hospitals Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors are grateful for funding support provided by Wellcome Trust (209083/Z/17/Z to E.L.B., 221951/Z/20/Z to H.H. and 226083/Z/22/Z to C.W.) https://wellcome.org/grant-funding, the Medical Research Council (MRC Grant G1002279 to A.H.C., MR/S01165X/1 to H.H., and MR/S005021/1, MRC ICGNMD), the Newlife Foundation for Disabled Children (A.H.C., L.E.R., and E.L.B.) https://newlifecharity.co.uk/, and the Academy of Medical Sciences (SGL029\1079 to L.E.R.). This work was also supported by GP2 ASAP, Michael J. Fox Foundation (MJFF), The Rosetrees Trust, MSA Trust, MSA Coalition, Brain Research UK, Sparks GOSH Charity, and Muscular Dystrophy UK (MDUK). The authors are also grateful for funding support provided by King Abdullah International Medical Research Center (NRC23R/177/02 to M.U.), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Germany’s Excellence Strategy (EXC-2049-390688087 to V.H.), the German Research Foundation (DFG) VO (2138/7-1 grant 469177153 to B.V.), and the European Union’s Seventh Framework Program for research, technological development and demonstration (grant 608473 to H.T.). B.V. is a member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/ 739516). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
2025-01-202025-01-202025-09-29Bibliographically approved