Advertisement

Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome

Published:September 09, 2022DOI:https://doi.org/10.1016/j.gim.2022.07.024

      ABSTRACT

      Purpose

      RABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.

      Methods

      Through GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped.

      Results

      We report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly.

      Conclusion

      Collectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      ACMG Member Login

      Are you an ACMG Member? Sign in for online access.

      Subscribe:

      Subscribe to Genetics in Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Cuif M.H.
        • Possmayer F.
        • Zander H.
        • et al.
        Characterization of GAPCenA, a GTPase activating protein for Rab6, part of which associates with the centrosome.
        EMBO J. 1999; 18: 1772-1782https://doi.org/10.1093/emboj/18.7.1772
        • Opdam F.J.
        • Echard A.
        • Croes H.J.
        • et al.
        The small GTPase Rab6B, a novel Rab6 subfamily member, is cell-type specifically expressed and localised to the Golgi apparatus.
        J Cell Sci. 2000; 113: 2725-2735https://doi.org/10.1242/jcs.113.15.2725
        • Kanno E.
        • Ishibashi K.
        • Kobayashi H.
        • Matsui T.
        • Ohbayashi N.
        • Fukuda M.
        Comprehensive screening for novel rab-binding proteins by GST pull-down assay using 60 different mammalian Rabs.
        Traffic. 2010; 11: 491-507https://doi.org/10.1111/j.1600-0854.2010.01038.x
        • Frasa M.A.M.
        • Koessmeier K.T.
        • Ahmadian M.R.
        • Braga V.M.M.
        Illuminating the functional and structural repertoire of human TBC/RABGAPs.
        Nat Rev Mol Cell Biol. 2012; 13 (Published correction appears in Nat Rev Mol Cell Biol. 2012;13(7):476): 67-73
        • Goud B.
        • Zahraoui A.
        • Tavitian A.
        • Saraste J.
        Small GTP-binding protein associated with Golgi cisternae.
        Nature. 1990; 345: 553-556https://doi.org/10.1038/345553a0
        • Antony C.
        • Cibert C.
        • Géraud G.
        • et al.
        The small GTP-binding protein rab6p is distributed from medial Golgi to the trans-Golgi network as determined by a confocal microscopic approach.
        J Cell Sci. 1992; 103: 785-796https://doi.org/10.1242/jcs.103.3.785
        • Martinez O.
        • Antony C.
        • Pehau-Arnaudet G.
        • Berger E.G.
        • Salamero J.
        • Goud B.
        GTP-bound forms of rab6 induce the redistribution of Golgi proteins into the endoplasmic reticulum.
        Proc Natl Acad Sci U S A. 1997; 94: 1828-1833https://doi.org/10.1073/pnas.94.5.1828
        • Girod A.
        • Storrie B.
        • Simpson J.C.
        • et al.
        Evidence for a COP-I-independent transport route from the Golgi complex to the endoplasmic reticulum.
        Nat Cell Biol. 1999; 1: 423-430https://doi.org/10.1038/15658
        • White J.
        • Johannes L.
        • Mallard F.
        • et al.
        Rab6 coordinates a novel Golgi to ER retrograde transport pathway in live cells.
        J Cell Biol. 1999; 147 (Published correction appears in J Cell Biol. 2000;148(1):205): 743-760
        • Mallard F.
        • Tang B.L.
        • Galli T.
        • et al.
        Early/recycling endosomes-to-TGN transport involves two SNARE complexes and a Rab6 isoform.
        J Cell Biol. 2002; 156: 653-664https://doi.org/10.1083/jcb.200110081
        • Kawasaki N.
        • Isogaya K.
        • Dan S.
        • et al.
        TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling.
        Cell Discov. 2018; 4: 1https://doi.org/10.1038/s41421-017-0001-2
        • Ryder E.
        • Doe B.
        • Gleeson D.
        • et al.
        Rapid conversion of EUCOMM/KOMP-CSD alleles in mouse embryos using a cell-permeable Cre recombinase.
        Transgen Res. 2014; 23: 177-185https://doi.org/10.1007/s11248-013-9764-x
        • Gailus-Durner V.
        • Fuchs H.
        • Becker L.
        • et al.
        Introducing the German Mouse Clinic: open access platform for standardized phenotyping.
        Nat Methods. 2005; 2: 403-404https://doi.org/10.1038/nmeth0605-403
        • Fuchs H.
        • Aguilar-Pimentel J.A.
        • Amarie O.V.
        • et al.
        Understanding gene functions and disease mechanisms: phenotyping pipelines in the German Mouse Clinic.
        Behav Brain Res. 2018; 352: 187-196https://doi.org/10.1016/j.bbr.2017.09.048
        • Parmenter M.D.
        • Gray M.M.
        • Hogan C.A.
        • et al.
        Genetics of skeletal evolution in unusually large mice from Gough Island.
        Genetics. 2016; 204: 1559-1572https://doi.org/10.1534/genetics.116.193805
        • Fuchs H.
        • Gailus-Durner V.
        • Adler T.
        • et al.
        Mouse phenotyping.
        Methods. 2011; 53: 120-135https://doi.org/10.1016/j.ymeth.2010.08.006
        • Kvarnung M.
        • Taylan F.
        • Nilsson D.
        • et al.
        Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy.
        Clin Genet. 2016; 89: 99-103https://doi.org/10.1111/cge.12565
      1. Sundberg JP, Woolcott BL, Cunlifee-Beamer T, Brown KS, Bronson R. Spontaneous hydrocephalus in inbred strains of mice. The Jackson Laboratory. Published April 01, 1991. Accessed July 15, 2022. https://www.jax.org/news-and-insights/1991/april/spontaneous-hydrocephalus-in-inbred-strains-of-mice

        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the association for molecular pathology.
        Genet Med. 2015; 17: 405-424https://doi.org/10.1038/gim.2015.30
        • Costa-Mattioli M.
        • Monteggia L.M.
        mTOR complexes in neurodevelopmental and neuropsychiatric disorders.
        Nat Neurosci. 2013; 16: 1537-1543https://doi.org/10.1038/nn.3546
        • Handley M.T.
        • Morris-Rosendahl D.J.
        • Brown S.
        • et al.
        Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in Warburg micro syndrome and Martsolf syndrome.
        Hum Mutat. 2013; 34: 686-696https://doi.org/10.1002/humu.22296
        • Imagawa E.
        • Fukai R.
        • Behnam M.
        • et al.
        Two novel homozygous RAB3GAP1 mutations cause Warburg micro syndrome.
        Hum Genome Var. 2015; 215034https://doi.org/10.1038/hgv.2015.34
        • Davey J.R.
        • Humphrey S.J.
        • Junutula J.R.
        • et al.
        TBC1D13 is a RAB35 specific GAP that plays an important role in GLUT4 trafficking in adipocytes.
        Traffic. 2012; 13: 1429-1441https://doi.org/10.1111/j.1600-0854.2012.01397.x