Skip to main content
SpringerLink
Log in

Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and saggy in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic.

Methods

In this study, we reported a case of a Han-Chinese male newborn with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the novel variant, and their parents were verified by Sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function.

Results

The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the newborn carried a non-canonical splicing-site variant c.117 + 5G > T, p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of the ATP6V0A2 gene.

Conclusions

In this study, it was identified that ATP6V0A2 gene c. 117 + 5G > T may be the cause of the disease. The non-canonical splicing variants of ATP6V0A2 gene were rarely reported in the past, and this variant expanded the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the level of evidence for the pathogenicity of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to patient confidentiality but are available from the corresponding author on reasonable request.

References

  1. GeneReviews® (1993) Seattle (WA). University of Washington, Seattle

    Google Scholar 

  2. Mohamed M, Voet M, Gardeitchik T, Morava E (2014) Cutis Laxa. Adv Exp Med Biol 802:161–184

    Article  CAS  PubMed  Google Scholar 

  3. Morava E, Guillard M, Lefeber DJ, Wevers RA (2009) Autosomal recessive cutis laxa syndrome revisited. Eur J Hum Genet 17(9):1099–1110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Patton MA, Tolmie J, Ruthnum P, Bamforth S, Baraitser M, Pembrey M (1987) Congenital cutis laxa with retardation of growth and development. J Med Genet 24(9):556–561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rahmati M, Yazdanparast M, Jahanshahi K, Zakeri M (2015) Congenital Cutis Laxa Type 2 Associated with Recurrent Aspiration Pneumonia and Growth Delay: Case Report. Electron Physician 7(6):1391–1393

    PubMed  PubMed Central  Google Scholar 

  6. Reisner SH, Seelenfreund M, Ben-Bassat M (1971) Cutis laxa associated with severe intrauterine growth retardation and congenital dislocation of the hip. Acta Paediatr Scand 60(3):357–360

    Article  CAS  PubMed  Google Scholar 

  7. Van Maldergem L, Yuksel-Apak M, Kayserili H et al (2008) Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type. Neurology 71(20):1602–1608

    Article  PubMed  Google Scholar 

  8. Fischer-Zirnsak B, Escande-Beillard N, Ganesh J et al (2015) Recurrent De Novo mutations affecting Residue Arg138 of pyrroline-5-Carboxylate synthase cause a progeroid form of autosomal-Dominant Cutis Laxa. Am J Hum Genet 97(3):483–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kornak U, Reynders E, Dimopoulou A et al (2008) Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 40(1):32–34

    Article  CAS  PubMed  Google Scholar 

  10. Hucthagowder V, Morava E, Kornak U et al (2009) Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. Hum Mol Genet 18(12):2149–2165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cohen R, Halevy A, Aharoni S et al (2016) Polymicrogyria and myoclonic epilepsy in autosomal recessive cutis laxa type 2A. Neurogenetics 17(4):251–257

    Article  CAS  PubMed  Google Scholar 

  12. Kariminejad A, Afroozan F, Bozorgmehr B et al (2017) Discriminative features in three autosomal recessive Cutis Laxa syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica. Int J Mol Sci. 18(3)

  13. Smith AN, Lovering RC, Futai M, Takeda J, Brown D, Karet FE (2003) Revised nomenclature for mammalian vacuolar-type H+ -ATPase subunit genes. Mol Cell 12(4):801–803

    Article  CAS  PubMed  Google Scholar 

  14. Bahena-Bahena D, López-Valdez J, Raymond K et al (2014) ATP6V0A2 mutations present in two Mexican mestizo children with an autosomal recessive cutis laxa syndrome type IIA. Mol Genet Metab Rep 1:203–212

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kumar R, Sharda S, Soni V, Nambiyar K (2017) Autosomal recessive Cutis Laxa type II: report of Novel Mutation in a child. Indian Dermatol Online J 8(5):352–354. https://doi.org/10.4103/idoj.IDOJ_334_16

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang P, Wang X, Gao Z, Liu X, Chen Q (2018) Zhonghua Yi Xue Yi Chuan Xue Za Zhi 35(1):100–103. https://doi.org/10.3760/cma.j.issn.1003-9406.2018.01.023. [Clinical and genetic analysis of a patient with cutis laxa]

  17. Richards S, Aziz N, Bale S et al (2015) 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 17(5):405–424

    Article  PubMed  PubMed Central  Google Scholar 

  18. Beyens A, Moreno-Artero E, Bodemer C, Cox H, Gezdirici A, Yilmaz Gulec E et al (2019) ATP6V0A2-related cutis laxa in 10 novel patients: focus on clinical variability and expansion of the phenotype. Exp Dermatol 28:1142–1145

    Article  CAS  PubMed  Google Scholar 

  19. Zaman Q, Iftikhar A, Rehman G, Khan Q, Najumuddin A, Jan et al (2023) Two novel homozygous variants of ATP6V0A2 and ALDH18A1 lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families. J Gene Med 25:e3522

    Article  CAS  PubMed  Google Scholar 

  20. Shafagh Shishavan N, Morovvati S (2023) A novel deletion mutation in the ATP6V0A2 gene in an Iranian patient affected by autosomal recessive cutis laxa. Ir J Med Sci 192:2279–2282

    Article  CAS  PubMed  Google Scholar 

  21. Karacan İ, Diz Küçükkaya R, Karakuş FN et al (2019) A novel ATP6V0A2 mutation causing recessive Cutis Laxa with unusual manifestations of bleeding diathesis and defective Wound Healing. Turk J Haematol 36(1):29–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Morlino S, Nardella G, Castellana S et al (2021) Review of clinical and molecular variability in autosomal recessive cutis laxa 2A. Am J Med Genet A 185(3):955–965

    Article  CAS  PubMed  Google Scholar 

  23. Guillard M, Dimopoulou A, Fischer B et al (2009) Vacuolar H+-ATPase meets glycosylation in patients with cutis laxa. Biochim Biophys Acta 1792(9):903–914

    Article  CAS  PubMed  Google Scholar 

  24. Fischer B, Dimopoulou A, Egerer J et al (2012) Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Hum Genet 131(11):1761–1773

    Article  CAS  PubMed  Google Scholar 

  25. Jaeken J, Hennet T, Matthijs G, Freeze HH (2009) CDG nomenclature: time for a change. Biochim Biophys Acta 1792(9):825–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mohamed M, Kouwenberg D, Gardeitchik T, Kornak U, Wevers RA, Morava E (2011) Metabolic cutis laxa syndromes. J Inherit Metab Dis 34(4):907–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bogdańska A, Lipiński P, Szymańska-Rożek P, Jezela-Stanek A, Rokicki D, Socha P et al (2021) Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up. Orphanet J Rare Dis 16:17

    Article  PubMed  PubMed Central  Google Scholar 

  28. Udono M, Fujii K, Harada G et al (2015) Impaired ATP6V0A2 expression contributes to golgi dispersion and glycosylation changes in senescent cells. Sci Rep 5:17342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Morava E, Wopereis S, Coucke P et al (2005) Defective protein glycosylation in patients with cutis laxa syndrome. Eur J Hum Genet 13(4):414–421

    Article  CAS  PubMed  Google Scholar 

  30. Gardeitchik T, Mohamed M, Fischer B et al (2014) Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa. Eur J Hum Genet 22(7):888–895

    Article  CAS  PubMed  Google Scholar 

  31. Raynor A, Vincent-Delorme C, Alaix AS, Cholet S, Dupré T, Vuillaumier-Barrot S et al (2021) Normal transferrin patterns in congenital disorders of glycosylation with Golgi homeostasis disruption: apolipoprotein C-III at the rescue, Clin. Chim Acta 519:285–290

    Article  CAS  Google Scholar 

  32. Medrano C, Vega A, Navarrete R, Ecay MJ, Calvo R, Pascual SI et al (2019) Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain. Clin Genet 95:615–626

    Article  CAS  PubMed  Google Scholar 

  33. Anna A, Monika G (2018) Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet 59(3):253–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Desviat LR, Pérez B, Ugarte M (2012) Minigenes to confirm exon skipping mutations. Methods Mol Biol 867:37–47

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Thanks for “funded by Tianjin Key Medical Discipline (Specialty) Construction Project”.

Funding

This study was supported by the Key Project of Tianjin Children’s Hospital, [grant number Y2020003]; the Natural Science Foundation of Tianjin, [grant number 21JCZDJC01030]; the Science and Technology project of Tianjin [grant number 21JCYBJC00370]; the Public Health and Technology Project of Tianjin, [grant number TJWJ2021ZD007] and the Natural Science Foundation of Tianjin, [grant number 21JCZDJC00390].

Author information

Author notes

  1. Ying Zhang, Mei Sun and Na Li should be considered joint first author..

Authors and Affiliations

  1. Graduate College of Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, 300070, China

    Ying Zhang, Mei Sun, Na Li & Yiran Zhao

  2. Department of Neonatology, Tianjin Children’s Hospital (Children’s Hospital of Tianjin University, No. 238 Longyan Road, Beichen District, Tianjin, 300134, China

    Na Li, Fang Zhang & Yang Liu

  3. Maternal and Child Health Hospital of Tangshan, No. 14 Jianshe south Road, Lu nan District, Tangshan City, Hebei Province, 063000, China

    Yiran Zhao

  4. Tianjin Children’s Hospital (Children’s Hospital of Tianjin University), No. 238 Longyan Road, Beichen District, Tianjin, 300134, China

    Jianbo Shu & Chunquan Cai

  5. Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, No. 238 Longyan Road, Beichen District, Tianjin, 300134, China

    Jianbo Shu & Chunquan Cai

  6. Tianjin Pediatric Research Institute, Tianjin Children’s Hospital, No. 238 Longyan Road, Beichen District, Tianjin, 300134, China

    Jianbo Shu & Chunquan Cai

Authors
  1. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Na Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yiran Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jianbo Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chunquan Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YL and CQC contributed to the study conception and design; Material preparation and data collection were performed by YZ and NL; Data Interpretation were performed by JBS and FZ; The first draft of the manuscript was written by YZ and MS; Literature Search were performed by MS, NL and YRZ; All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jianbo Shu, Yang Liu or Chunquan Cai.

Ethics declarations

Ethics approval and consent to Participate

Our article was published with the consent of the child’s parents and approved by the Ethics Committee of Tianjin Children’s hospital(Approval number: 2021-KY-03).

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Sun, M., Li, N. et al. Identification of a novel intronic variant of ATP6V0A2 in a Han-Chinese family with cutis laxa. Mol Biol Rep 51, 498 (2024). https://doi.org/10.1007/s11033-024-09446-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-024-09446-0

Keywords

Search

Navigation