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Neurogenetics
04, 2023;24 (2): 79-93.

INPP4A-related genetic and phenotypic spectrum and functional relevance of subcellular targeting of INPP4A isoforms.

Laura Hecher, Frederike L Harms, Jasmin Lisfeld, Malik Alawi, Jonas Denecke, Kerstin Kutsche
Author Information
  1. Laura Hecher: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  2. Frederike L Harms: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  3. Jasmin Lisfeld: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  4. Malik Alawi: Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  5. Jonas Denecke: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  6. Kerstin Kutsche: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. kkutsche@uke.de. ORCID
PMID: 36653678 DOI: 10.1007/s10048-023-00709-9

Abstract

Type I inositol polyphosphate-4-phosphatase (INPP4A) belongs to the group of phosphoinositide phosphatases controlling proliferation, apoptosis, and endosome function by hydrolyzing phosphatidylinositol 3,4-bisphosphate. INPP4A produces multiple transcripts encoding shorter and longer INPP4A isoforms with hydrophilic or hydrophobic C-terminus. Biallelic INPP4A truncating variants cause a spectrum of neurodevelopmental disorders ranging from moderate intellectual disability to postnatal microcephaly with developmental and epileptic encephalopathy and (ponto)cerebellar hypoplasia. We report a girl with the novel homozygous INPP4A variant NM_001134224.2:c.2840del/p.(Gly947Glufs*12) (isoform d). She presented with postnatal microcephaly, global developmental delay, visual impairment, myoclonic seizures, and pontocerebellar hypoplasia and died at the age of 27 months. The level of mutant INPP4A mRNAs in proband-derived leukocytes was comparable to controls suggesting production of C-terminally altered INPP4A isoforms. We transiently expressed eGFP-tagged INPP4A isoform a (NM_004027.3) wildtype and p.(Gly908Glufs*12) mutant [p.(Gly947Glufs*12) according to NM_001134224.2] as well as INPP4A isoform b (NM_001566.2) wildtype and p.(Asp915Alafs*2) mutant, previously reported in family members with moderate intellectual disability, in HeLa cells and determined their subcellular distributions. While INPP4A isoform a was preferentially found in perinuclear clusters co-localizing with the GTPase Rab5, isoform b showed a net-like distribution, possibly localizing near and/or on microtubules. Quantification of intracellular localization patterns of the two INPP4A mutants revealed significant differences compared with the respective wildtype and similarity with each other. Our data suggests an important non-redundant function of INPP4A isoforms with hydrophobic or hydrophilic C-terminus in the brain.

Keywords

Alternative splicing Endocytosis Phosphatidylinositol 3-phosphate Pontocerebellar hypoplasia Vesicular traffic

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MeSH Term

Child, Preschool
Female
Humans
Cerebellum
HeLa Cells
Intellectual Disability
Microcephaly
Phosphoric Monoester Hydrolases

Chemicals

Phosphoric Monoester Hydrolases
phosphatidylinositol-3,4-bisphosphate 4-phosphatase
Case Reports Journal Article Research Support, Non-U.S. Gov't

Word Cloud

Created with Highcharts 10.0.0INPP4Aisoformisoformshypoplasiamutantwildtypefunction3hydrophilichydrophobicC-terminusspectrummoderateintellectualdisabilitypostnatalmicrocephalydevelopmentalNM_001134224Gly947Glufs*12pbsubcellularTypeinositolpolyphosphate-4-phosphatasebelongsgroupphosphoinositidephosphatasescontrollingproliferationapoptosisendosomehydrolyzingphosphatidylinositol4-bisphosphateproducesmultipletranscriptsencodingshorterlongerBiallelictruncatingvariantscauseneurodevelopmentaldisordersrangingepilepticencephalopathypontocerebellarreportgirlnovelhomozygousvariant2:c2840del/pdpresentedglobaldelayvisualimpairmentmyoclonicseizurespontocerebellardiedage27 monthslevelmRNAsproband-derivedleukocytescomparablecontrolssuggestingproductionC-terminallyalteredtransientlyexpressedeGFP-taggedNM_004027Gly908Glufs*12[paccording2]wellNM_0015662Asp915Alafs*2previouslyreportedfamilymembersHeLacellsdetermineddistributionspreferentiallyfoundperinuclearclustersco-localizingGTPaseRab5showednet-likedistributionpossiblylocalizingnearand/ormicrotubulesQuantificationintracellularlocalizationpatternstwomutantsrevealedsignificantdifferencescomparedrespectivesimilaritydatasuggestsimportantnon-redundantbrainINPP4A-relatedgeneticphenotypicfunctionalrelevancetargetingAlternativesplicingEndocytosisPhosphatidylinositol3-phosphatePontocerebellarVesiculartraffic

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