DOORS syndrome and a recurrent truncating ATP6V1B2 variant

A Correction to this article was published on 15 September 2020

This article has been updated (view changelog)

Abstract

Purpose

Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant.

Methods

Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants.

Results

We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found.

Conclusion

We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.

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Fig. 1: Physical features of individuals with DOORS syndrome.
Fig. 2: Location of the known pathogenic variants in ATP6V1B2.
Fig. 3: Location of the variants in V-ATPase.

Change history

  • 11 September 2020

    In the original version of this Article, the affiliation details for Guillermo Pacheco-Cuellar, Jessica Tardif, Maria Vittoria Camurri, Sirinart Molidperee and Philippe M. Campeau were incorrectly given. They have now been corrected in both the PDF and HTML versions of the Article.

References

  1. 1.

    Campeau PM, Kasperaviciute D, Lu JT, et al. The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol. 2014;13:44–58.

    CAS  Article  Google Scholar 

  2. 2.

    Yuan Y, Zhang J, Chang Q, et al. De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome. Cell Res. 2014;24:1370–1373.

    CAS  Article  Google Scholar 

  3. 3.

    Menendez I, Carranza C, Herrera M, et al. Dominant deafness-onychodystrophy syndrome caused by an ATP6V1B2 mutation. Clin Case Rep. 2017;5:376–379.

    Article  Google Scholar 

  4. 4.

    Kortum F, Caputo V, Bauer CK, et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann–Laband syndrome. Nat Genet. 2015;47:661–667.

    Article  Google Scholar 

  5. 5.

    Popp B, Ekici AB, Thiel CT, et al. Exome Pool-Seq in neurodevelopmental disorders. Eur J Hum Genet. 2017;25:1364–1376.

    CAS  Article  Google Scholar 

  6. 6.

    Shaw M, Winczewska-Wiktor A, Badura-Stronka M, et al. EXOME REPORT: novel mutation in ATP6V1B2 segregating with autosomal dominant epilepsy, intellectual disability and mild gingival and nail abnormalities. Eur J Med Genet. 2020;63:103799.

    Article  Google Scholar 

  7. 7.

    Vind-Kezunovic D, Torring PM. A Danish family with dominant deafness-onychodystrophy syndrome. J Dermatol Case Rep. 2013;7:125–128.

    Article  Google Scholar 

  8. 8.

    White SM, Fahey M. Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome. Am J Med Genet A. 2011;155:2512–2515.

    Article  Google Scholar 

  9. 9.

    Murakami Y, Nguyen TTM, Baratang N, et al. Mutations in PIGB cause an inherited GPI biosynthesis defect with an axonal neuropathy and metabolic abnormality in severe cases. Am J Hum Genet. 2019;105:384–394.

    CAS  Article  Google Scholar 

  10. 10.

    Bauer CK, Schneeberger PE, Kortum F, et al. Gain-of-function mutations in KCNN3 encoding the small-conductance Ca(2+)-activated K(+) channel SK3 cause Zimmermann–Laband syndrome. Am J Hum Genet. 2019;104:1139–1157.

    CAS  Article  Google Scholar 

  11. 11.

    Kariminejad A, Ajeawung NF, Bozorgmehr B, et al. Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails. J Hum Genet. 2017;62:465–471.

    CAS  Article  Google Scholar 

  12. 12.

    Campeau PM, Hennekam RC, group Dsc. DOORS syndrome: phenotype, genotype and comparison with Coffin–Siris syndrome. Am J Med Genet C Semin Med Genet. 2014;166C:327–332.

    Article  Google Scholar 

  13. 13.

    Mucha BE, Hennekam RCM, Sisodiya S, Campeau PM. TBC1D24-related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle, WA: University of Washington; 1993.

  14. 14.

    Robinson GC, Miller JR, Bensimon JR. Familial ectodermal dysplasia with sensori-neural deafness and other anomalies. Pediatrics. 1962;30:797–802.

    Google Scholar 

  15. 15.

    Kondoh T, Tsuru A, Matsumoto T, Matsuzaka T, Tsuji Y. Autosomal dominant onychodystrophy and congenital sensorineural deafness. J Hum Genet. 1999;44:60–62.

    CAS  Article  Google Scholar 

  16. 16.

    James AW, Miranda SG, Culver K, Hall BD, Golabi M. DOOR syndrome: clinical report, literature review and discussion of natural history. Am J Med Genet A. 2007;143A:2821–2831.

    CAS  Article  Google Scholar 

  17. 17.

    Finelli MJ, Aprile D, Castroflorio E, et al. The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons. Hum Mol Genet. 2019;28:584–597.

    CAS  Article  Google Scholar 

  18. 18.

    Fernandes AC, Uytterhoeven V, Kuenen S, et al. Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration. J Cell Biol. 2014;207:453–462.

    CAS  Article  Google Scholar 

  19. 19.

    Uytterhoeven V, Kuenen S, Kasprowicz J, Miskiewicz K, Verstreken P. Loss of Skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins. Cell. 2011;145:117–132.

    CAS  Article  Google Scholar 

  20. 20.

    Fischer B, Lüthy K, Paesmans J, et al. Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol. 2016;23:965–973.

    CAS  Article  Google Scholar 

  21. 21.

    Luthy K, Mei D, Fischer B, et al. TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model. Brain. 2019;142:2319–2335.

    Article  Google Scholar 

  22. 22.

    Vavassori S, Mayer A. A new life for an old pump: V-ATPase and neurotransmitter release. J Cell Biol. 2014;205:7–9.

    CAS  Article  Google Scholar 

  23. 23.

    Bell S, Rousseau J, Peng H, et al. Mutations in ACTL6B cause neurodevelopmental deficits and epilepsy and lead to loss of dendrites in human neurons. Am J Hum Genet. 2019;104:815–834.

    CAS  Article  Google Scholar 

  24. 24.

    Zhao W, Gao X, Qiu S, et al. A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability. EBioMedicine. 2019;45:408–421.

    Article  Google Scholar 

  25. 25.

    Kimble JE, White JG. On the control of germ cell development in Caenorhabditis elegans. Dev Biol. 1981;81:208–219.

    CAS  Article  Google Scholar 

  26. 26.

    Merkulova M, Paunescu TG, Azroyan A, Marshansky V, Breton S, Brown D. Mapping the H(+) (V)-ATPase interactome: identification of proteins involved in trafficking, folding, assembly and phosphorylation. Sci Rep. 2015;5:14827.

    CAS  Article  Google Scholar 

  27. 27.

    Merkulova M, Paunescu TG, Nair AV, et al. Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice. Am J Physiol Renal Physiol. 2018;315:F173–F185.

    CAS  Article  Google Scholar 

  28. 28.

    Huttlin EL, Ting L, Bruckner RJ, et al. The BioPlex Network: a systematic exploration of the human interactome. Cell. 2015;162:425–440.

    CAS  Article  Google Scholar 

  29. 29.

    Doyle T, Moncorge O, Bonaventure B, et al. The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry. Nat Microbiol. 2018;3:1369–1376.

    CAS  Article  Google Scholar 

  30. 30.

    Marshansky V, Futai M. The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Curr Opin Cell Biol. 2008;20:415–426.

    CAS  Article  Google Scholar 

  31. 31.

    Fassio A, Esposito A, Kato M, et al. De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy. Brain. 2018;141:1703–1718.

    Article  Google Scholar 

  32. 32.

    Mucha BE, Banka S, Ajeawung NF, et al. A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay. Genet Med. 2019;21:1058–1064.

    CAS  Article  Google Scholar 

  33. 33.

    Van Damme T, Gardeitchik T, Mohamed M, et al. Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa. Am J Hum Genet. 2017;100:216–227.

    Article  Google Scholar 

  34. 34.

    Abbas YM, Wu D, Bueler SA, Robinson CV, Rubinstein JL. Structure of V-ATPase from the mammalian brain. Science. 2020;367:1240–1246.

    CAS  Article  Google Scholar 

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Acknowledgements

We thank all families. This study was funded in part by Canadian Institutes of Health Research and Fonds de la Recherche du Québec–Santé awards to P.M.C.

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Correspondence to Philippe M. Campeau MD.

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Beauregard-Lacroix, E., Pacheco-Cuellar, G., Ajeawung, N.F. et al. DOORS syndrome and a recurrent truncating ATP6V1B2 variant. Genet Med (2020). https://doi.org/10.1038/s41436-020-00950-9

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Keywords

  • DOORS syndrome
  • DDOD syndrome
  • ATP6V1B2 gene
  • TBC1D24 gene
  • exome sequencing

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