Top

Published in:

Open Access 01-12-2021 | Hypertrichosis | Case report

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report

Authors: Raziyeh Khalesi, Ehsan Razmara, Golareh Asgaritarghi, Ali Reza Tavasoli, Yasser Riazalhosseini, Daniel Auld, Masoud Garshasbi

Published in: BMC Neurology | Issue 1/2021

Abstract

Background

The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients.

Case presentation

A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant—NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)—in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes.

Conclusions

Due to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the “RABopathies” term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1.

Available only for authorised users

Bem D, Yoshimura S-I, Nunes-Bastos R, Bond FF, Kurian MA, Rahman F, et al. Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Am J Hum Genet. 2011;88(4):499–507. https://doi.org/10.1016/j.ajhg.2011.03.012.

Dursun F, Güven A, Morris-Rosendahl D. Warburg micro syndrome. J Pediatr Endocrinol Metab. 2012;25(3–4):379–82. https://doi.org/10.1515/jpem-2011-0459.

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, et al. New RAB3GAP1 mutations in patients with Warburg micro syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010;18(10):1100–6. https://doi.org/10.1038/ejhg.2010.79.

Borck G, Wunram H, Steiert A, Volk AE, Körber F, Roters S, et al. A homozygous RAB3GAP2 mutation causes Warburg micro syndrome. Hum Genet. 2011;129(1):45–50. https://doi.org/10.1007/s00439-010-0896-2.

Liegel RP, Handley MT, Ronchetti A, Brown S, Langemeyer L, Linford A, et al. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013;93(6):1001–14. https://doi.org/10.1016/j.ajhg.2013.10.011.

Aligianis IA, Morgan NV, Mione M, Johnson CA, Rosser E, Hennekam RC, et al. Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am J Hum Genet. 2006;78(4):702–7. https://doi.org/10.1086/502681.

Fukui K, Sasaki T, Imazumi K, Matsuura Y, Nakanishi H, Takai Y. Isolation and characterization of a GTPase activating protein specific for the Rab3 subfamily of small G proteins. J Biol Chem. 1997;272(8):4655–8. https://doi.org/10.1074/jbc.272.8.4655.

Ng EL, Tang BL. Rab GTPases and their roles in brain neurons and glia. Brain Res Rev. 2008;58(1):236–46. https://doi.org/10.1016/j.brainresrev.2008.04.006.

Coppola T, Perret-Menoud V, Lüthi S, Farnsworth CC, Glomset JA, Regazzi R. Disruption of Rab3–calmodulin interaction, but not other effector interactions, prevents Rab3 inhibition of exocytosis. EMBO J. 1999;18(21):5885–91. https://doi.org/10.1093/emboj/18.21.5885.

10.

Tahara S, Sanno N, Teramoto A, Osamura RY. Expression of Rab3, a Ras-related GTP-binding protein, in human nontumorous pituitaries and pituitary adenomas. Mod Pathol. 1999;12(6):627–34.

11.

Iwasaki K, Toyonaga R. The Rab3 GDP/GTP exchange factor homolog AEX-3 has a dual function in synaptic transmission. EMBO J. 2000;19(17):4806–16. https://doi.org/10.1093/emboj/19.17.4806.

12.

Khvotchev MV, Ren M, Takamori S, Jahn R, Südhof TC. Divergent functions of neuronal Rab11b in Ca2+−regulated versus constitutive exocytosis. J Neurosci. 2003;23(33):10531–9. https://doi.org/10.1523/jneurosci.23-33-10531.2003.

13.

Handley MT, Aligianis IA. RAB3GAP1, RAB3GAP2 and RAB18: disease genes in Micro and Martsolf syndromes. Biochem Soc Trans. 2012;40(6). https://doi.org/10.1042/bst20120169.

14.

Shotelersuk V, Desudchit T, Suwanwela N. Postnatal growth failure, microcephaly, mental retardation, cataracts, large joint contractures, osteoporosis, cortical dysplasia, and cerebellar atrophy. Am J Med Genet A. 2003;116(2):164–9. https://doi.org/10.1002/ajmg.a.10067.

15.

Dajani DR, Llabre MM, Nebel MB, Mostofsky SH, Uddin LQ. Heterogeneity of executive functions among comorbid neurodevelopmental disorders. Sci Rep. 2016;6(1):36566. https://doi.org/10.1038/srep36566.

16.

Gilani N, Razmara E, Ozaslan M, Abdulzahra IK, Arzhang S, Tavasoli AR, et al. A novel deletion variant in CLN3 with highly variable expressivity is responsible for juvenile neuronal ceroid lipofuscinoses. Acta Neurol Belg. 2021:1–12. https://doi.org/10.1007/s13760-021-01655-9.

17.

Soleimanipour F, Razmara E, Rahbarizadeh F, Fallahi E, Khodaeian M, Tavasoli AR, et al. A novel missense variant in the LMNB2 gene causes progressive myoclonus epilepsy. Acta Neurol Belg. 2021:1–9. https://doi.org/10.1007/s13760-021-01650-0.

18.

Razmara E, Azimi H, Tavasoli AR, Fallahi E, Sheida SV, Eidi M, et al. Novel neuroclinical findings of autosomal recessive primary microcephaly 15 in a consanguineous Iranian family. Eur J Med Genet. 2020;63(12):104096. https://doi.org/10.1016/j.ejmg.2020.104096.

19.

Garshasbi M, Mahmoudi M, Razmara E, Vojdanian M, Aslani S, Farhadi E, et al. Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS. Eur J Hum Genet. 2020;28(6):1–9. https://doi.org/10.1038/s41431-020-0573-4.

20.

Sherry ST, Ward M-H, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11. https://doi.org/10.1093/nar/29.1.308.

21.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. 1000 genome project data processing Subgroup. 2009. The sequence alignment/map format and samtools. Bioinformatics. 2009;25(16):2078–9. https://doi.org/10.1093/bioinformatics/btp352.

22.

Auer PL, Johnsen JM, Johnson AD, Logsdon BA, Lange LA, Nalls MA, et al. Imputation of exome sequence variants into population-based samples and blood-cell-trait-associated loci in African Americans: NHLBI GO exome sequencing project. Am J Hum Genet. 2012;91(5):794–808. https://doi.org/10.1016/j.ajhg.2012.08.031.

23.

Wang Q, Pierce-Hoffman E, Cummings BB, Alföldi J, Francioli LC, Gauthier LD, et al. Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes. Nat Commun. 2020;11(1):1–13. https://doi.org/10.1038/s41467-019-12438-5.

24.

Karczewski KJ, Weisburd B, Thomas B, Solomonson M, Ruderfer DM, Kavanagh D, et al. The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res. 2017;45(D1):D840–D5. https://doi.org/10.1093/nar/gkw971.

25.

Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812–4. https://doi.org/10.1093/nar/gkg509.

26.

Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;76(1):7.20. 1–7. 41. https://doi.org/10.1002/0471142905.hg0720s76.

27.

Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7(8):575–6. https://doi.org/10.1038/nmeth0810-575.

28.

Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015;31(16):2745–7. https://doi.org/10.1093/bioinformatics/btv195.

29.

Untergasser A, Nijveen H, Rao X, Bisseling T, Geurts R, Leunissen JA. Primer3Plus, an enhanced web interface to Primer3. Nucleic Acids Res. 2007;35(suppl_2):W71–W4. https://doi.org/10.1093/nar/gkm306.

30.

Glaser F, Pupko T, Paz I, Bell RE, Bechor-Shental D, Martz E, et al. ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics. 2003;19(1):163–4. https://doi.org/10.1093/bioinformatics/19.1.163.

31.

Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu Y, et al. The UCSC genome browser database. Nucleic Acids Res. 2003;31(1):51–4. https://doi.org/10.1093/nar/gkg129.

32.

Wiel L, Baakman C, Gilissen D, Veltman JA, Vriend G, Gilissen C. MetaDome: pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum Mutat. 2019;40(8):1030–8. https://doi.org/10.1002/humu.23798.

33.

Fattahi Z, Beheshtian M, Mohseni M, Poustchi H, Sellars E, Nezhadi SH, et al. Iranome: a catalog of genomic variations in the Iranian population. Hum Mutat. 2019;40(11):1968–84. https://doi.org/10.1002/humu.23880.

34.

Daneshjoo O, Garshasbi M. Novel compound heterozygote mutations in the ATP7B gene in an Iranian family with Wilson disease: a case report. J Med Case Rep. 2018;12(1):1–7. https://doi.org/10.1186/s13256-018-1608-0.

35.

Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37(9):e67–e. https://doi.org/10.1093/nar/gkp215.

36.

Spradling AC, Stern D, Beaton A, Rhem EJ, Laverty T, Mozden N, et al. The Berkeley Drosophila genome project gene disruption project: single P-element insertions mutating 25% of vital Drosophila genes. Genetics. 1999;153(1):135–77.

37.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods. 2001;25(4):402–8. https://doi.org/10.1006/meth.2001.1262.

38.

Hayat Nosaeid M, Mahdian R, Jamali S, Maryami F, Babashah S, Maryami F, et al. Validation and comparison of two quantitative real-time PCR assays for direct detection of DMD/BMD carriers. Clin Biochem. 2009;42(12):1291–9. https://doi.org/10.1016/j.clinbiochem.2009.04.016.

39.

Soreq L, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, et al. Major shifts in glial regional identity are a transcriptional hallmark of human brain aging. Cell Rep. 2017;18(2):557–70. https://doi.org/10.1016/j.celrep.2016.12.011.

40.

Wang Q, Ding S-L, Li Y, Royall J, Feng D, Lesnar P, et al. The Allen mouse brain common coordinate framework: a 3D reference atlas. Cell. 2020;181(4):936–953.e20. https://doi.org/10.1016/j.cell.2020.04.007.

41.

Xiong J, Ren J, Luo L, Horowitz M. Mapping histological slice sequences to the Allen mouse brain atlas without 3D reconstruction. Front Neuroinform. 2018;12:93. https://doi.org/10.3389/fninf.2018.00093.

42.

Hill DP, Begley DA, Finger JH, Hayamizu TF, McCright IJ, Smith CM, et al. The mouse Gene Expression Database (GXD): updates and enhancements. Nucleic Acids Res. 2004;32(suppl_1):D568–D71. https://doi.org/10.1093/nar/gkh069.

43.

Kabzinska D, Mierzewska H, Senderek J, Kochanski A. Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy. Folia Neuropathol. 2016;3:273–81. https://doi.org/10.5114/fn.2016.62537.

44.

Hozhabri H, Talebi M, Mehrjardi MY, De Luca A, Dehghani M. Martsolf syndrome with novel mutation in the TBC1D20 gene in a family from Iran. Am J Med Genet A. 2020;182(5):957–61. https://doi.org/10.1002/ajmg.a.61543.

45.

Geyer M, Wittinghofer A. GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins. Curr Opin Struct Biol. 1997;7(6):786–92. https://doi.org/10.1016/s0959-440x(97)80147-9.

46.

Pfeffer SR. Rab GTPases: master regulators of membrane trafficking. Curr Opin Cell Biol. 1994;6(4):522–6. https://doi.org/10.1016/0955-0674(94)90071-x.

47.

Ingmundson A, Delprato A, Lambright DG, Roy CR. Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature. 2007;450(7168):365–9. https://doi.org/10.1038/nature06336.

48.

Handley MT, Aligianis IA. RAB3GAP1, RAB3GAP2 and RAB18: disease genes in Micro and Martsolf syndromes. Biochem Soc Trans. 2012;40(6). https://doi.org/10.1042/bst20120169.

49.

Sakane A, Manabe S, Ishizaki H, Tanaka-Okamoto M, Kiyokage E, Toida K, et al. Rab3 GTPase-activating protein regulates synaptic transmission and plasticity through the inactivation of Rab3. Proc Natl Acad Sci. 2006;103(26):10029–34. https://doi.org/10.1073/pnas.0600304103.

50.

Tenawi S, Al Khudari R, Alasmar D. Novel mutation in the RAB3GAP1 gene, the first diagnosed Warburg Micro syndrome case in Syria. Oxford Med Case Rep. 2020;2020(4):omaa031. https://doi.org/10.1093/omcr/omaa031.

51.

Brogna S, Wen J. Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol. 2009;16(2):107–13. https://doi.org/10.1038/nsmb.1550.

52.

Roest PA, Roberts RG, Sugino S, van Ommen G-JB, den Dunnen JT. Protein truncation test (PTT) for rapid detection of translation-terminating mutations. Hum Mol Genet. 1993;2(10):1719–21. https://doi.org/10.1093/hmg/2.10.1719.

53.

Chang Y-F, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem. 2007;76(1):51–74. https://doi.org/10.1146/annurev.biochem.76.050106.093909.

54.

Asahina M, Endoh Y, Matsubayashi T, Fukuda T, Ogata T. Novel RAB3GAP1 compound heterozygous mutations in Japanese siblings with Warburg micro syndrome. Brain Dev. 2016;38(3):337–40. https://doi.org/10.1016/j.braindev.2015.09.006.

55.

Biesecker LG, Harrison SM. The ACMG/AMP reputable source criteria for the interpretation of sequence variants. Genet Med. 2018;20(12):1687–8. https://doi.org/10.1038/gim.2018.42.

56.

Gumus E. Case report of four siblings in Southeast Turkey with a novel RAB3GAP2 splice site mutation: Warburg micro syndrome or Martsolf syndrome? Ophthalmic Genet. 2018;39(3):391–5. https://doi.org/10.1080/13816810.2018.1432065.

57.

Koparir A, Karatas OF, Yilmaz SS, Suer I, Ozer B, Yuceturk B, et al. Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes. Am J Med Genet A. 2019;179(4):579–87. https://doi.org/10.1002/ajmg.a.61065.

Title: Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report
Authors: Raziyeh Khalesi
Ehsan Razmara
Golareh Asgaritarghi
Ali Reza Tavasoli
Yasser Riazalhosseini
Daniel Auld
Masoud Garshasbi
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Hypertrichosis
Published in: BMC Neurology / Issue 1/2021
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-021-02204-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report

Abstract

Background

Case presentation

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Case presentation

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Neurologists’ current practice and perspectives on communicating the diagnosis of a motor neurodegenerative condition: a UK survey

IL6 trans-signaling associates with ischemic stroke but not with atrial fibrillation

Differences in peripheral neuropathy in xeroderma pigmentosum complementation groups A and D as evaluated by nerve conduction studies

Coronavirus disease 2019 (COVID-19) can predispose young to Intracerebral hemorrhage: a retrospective observational study

Risk factors for postoperative ischemic complications in pediatric moyamoya disease

Intensive neurorehabilitation for patients with prolonged disorders of consciousness: protocol of a mixed-methods study focusing on outcomes, ethics and impact