Advertisement

Journal of Clinical Immunology

, Volume 38, Issue 4, pp 494–502 | Cite as

Insights into Mutation Effect in Three Poikiloderma with Neutropenia Patients by Transcript Analysis and Disease Evolution of Reported Patients with the Same Pathogenic Variants

  • Elisa A. Colombo
  • Nursel H. Elcioglu
  • Claudio Graziano
  • Pamela Farinelli
  • Elisabetta Di Fede
  • Iria Neri
  • Elena Facchini
  • Mariangela Greco
  • Cristina Gervasini
  • Lidia Larizza
Original Article
  • 83 Downloads

Abstract

Purpose

Poikiloderma with neutropenia (PN) is a genodermatosis currently described in 77 patients, all presenting with early-onset poikiloderma, neutropenia, and several additional signs. Biallelic loss-of-function mutations in USB1 gene are detected in all molecularly tested patients but genotype-phenotype correlation remains elusive. Cancer predisposition is recognized among PN features and pathogenic variants found in patients who developed early in life myelodysplasia (n = 12), acute myeloid leukemia (n = 2), and squamous cell carcinoma (n = 2) should be kept into account in management and follow-up of novel patients. This will hopefully allow achieving data clustered on specific mutations relevant to oncological surveillance of the carrier patients.

Methods

We describe the clinical features of three unreported PN patients and characterize their USB1 pathogenic variants by transcript analysis to get insights into the effect on the overall phenotype and disease evolution.

Results

A Turkish boy is homozygous for the c.531delA deletion, a recurrent mutation in Turkey; an adult Italian male is compound heterozygous for two nonsense mutations, c.243G>A and c.541C>T, while an Italian boy is homozygous for the splicing c.683_693+1del variant. The identified mutations have already been reported in PN patients who developed hematologic or skin cancer. Aberrant mRNAs of all four mutated alleles could be identified confirming that transcripts of USB1 main isoform either carrying stop codons or mis-spliced may at least partially escape nonsense-mediated decay.

Conclusions

Our study addresses the need of gathering insights on genotype-phenotype correlations in newly described PN patients, by transcript analysis and information on disease evolution of reported patients with the same pathogenic variants.

Keywords

Poikiloderma with neutropenia USB1 transcript analysis disease phenotype cancer predisposition 

Notes

Acknowledgements

We thank the patients and their families for their kind participation in this study.

Authorship Contributions

EAC interpreted the molecular results, drafted, revised, and approved the final version; NHE contributed with clinical data and biological samples of family no. #32, drafted the clinical paragraph, and approved the final version; CG contributed with clinical data and biological samples of family no. #49, drafted the clinical paragraph, and approved the final version; PF contributed with clinical data and biological samples of family no. #48, drafted the clinical paragraph, and approved the final version; EDF performed molecular analyses; IN contributed with clinical data and biological samples of family no. #49, drafted the clinical paragraph, and approved the final version; EF contributed with clinical data and biological samples of family no. #49, drafted the clinical paragraph, and approved the final version; MG contributed with clinical data and biological samples of family no. #48, drafted the clinical paragraph, and approved the final version; CG supported the molecular work and software access; LL conceived and coordinated the study, and drafted, revised, and approved the final version of the manuscript.

Funding Information

This work was supported by Italian Ministry of Health to Istituto Auxologico Italiano (LL- Ricerca Corrente 08C624).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

10875_2018_508_MOESM1_ESM.pdf (278 kb)
ESM 1 (PDF 277 kb)

References

  1. 1.
    Erickson RP. Southwestern Athabaskan (Navajo and Apache) genetic diseases. Genet Med. 1999;1:151–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Wang LL, Clericuzio C, Larizza L. Poikiloderma with neutropenia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. GeneReviews® [Internet]. Seattle (GA): University of Washington, Seattle; 1993–2017.Google Scholar
  3. 3.
    Porter WM, Hardman CM, Abdalla SH, Powles AV. Haematological disease in siblings with Rothmund-Thomson syndrome. Clin Exp Dermatol. 1999;24:452–4.CrossRefPubMedGoogle Scholar
  4. 4.
    Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I. Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome. Hum Mol Genet. 2010;19:4453–61.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rodgers W, Ancliff P, Ponting CP, Sanchez-Pulido L, Burns S, Hayman M, et al. Squamous cell carcinoma in a child with Clericuzio-type poikiloderma with neutropenia. Br J Dermatol. 2013;168:665–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Pianigiani E, De Aloe G, Andreassi A, Rubegni P, Fimiani M. Rothmund-Thomson syndrome (Thomson type) and myelodysplasia. Pediatr Dermatol. 2001;18:422–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Mostefai R, Morice-Picard F, Boralevi F, Sautarel M, Lacombe D, Stasia MJ, et al. Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco. Am J Med Genet A. 2008;146A(21):2762–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Colombo EA, Bazan JF, Negri G, Gervasini C, Elcioglu NH, Yucelten D, et al. Novel C16orf57 mutations in patients with poikiloderma with neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations. Orphanet J Rare Dis. 2012;7:7.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Patiroglu T, Akar HH. Clericuzio-type Poikiloderma with neutropenia syndrome in a Turkish family: a three report of siblings with mutation in the C16orf57 gene. Iran J Allergy Asthma Immunol. 2015;14:331–7.PubMedGoogle Scholar
  10. 10.
    Walne AJ, Collopy L, Cardoso S, Ellison A, Plagnol V, Albayrak C, et al. Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis. Haematologica. 2016;101:1180–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    El-Heis S, Godfrey KM. The role of genetic testing in hereditary poikiloderma: a case report. Glob Pediatr Health. 2017;4:1–3.Google Scholar
  12. 12.
    Volpi L, Roversi G, Colombo EA, Leijsten N, Concolino D, Calabria A, et al. Targeted next-generation sequencing appoints C16orf57 as Clericuzio-type poikiloderma with neutropenia gene. Am J Hum Genet. 2010;86:72–6.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Mroczek S, Krwawicz J, Kutner J, Lazniewski M, Kuciński I, Ginalski K, et al. C16orf57, a gene mutated in poikiloderma with neutropenia, encodes a putative phosphodiesterase responsible for the U6 snRNA 3′ end modification. Genes Dev. 2012;26:1911–25.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Shchepachev V, Wischnewski H, Missiaglia E, Soneson C, Azzalin CM. Mpn1, mutated in poikiloderma with neutropenia protein 1, is a conserved 3′-to-5′ RNA exonuclease processing U6 small nuclear RNA. Cell Rep. 2012;2:855–65.CrossRefPubMedGoogle Scholar
  15. 15.
    Hilcenko C, Simpson PJ, Finch AJ, Bowler FR, Churcher MJ, Jin L, et al. Aberrant 3′ oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia. Blood. 2013;121:1028–38.CrossRefPubMedGoogle Scholar
  16. 16.
    Didychuk AL, Montemayor EJ, Carrocci TJ, DeLaitsch AT, Lucarelli SE, Westler WM, et al. Usb1 controls U6 snRNP assembly through evolutionarily divergent cyclic phosphodiesterase activities. Nat Commun. 2017;8:497.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Concolino D, Roversi G, Muzzi GL, Sestito S, Colombo EA, Volpi L, et al. Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: delineation of the phenotype. Am J Med Genet A. 2010;152A:2588–94.CrossRefPubMedGoogle Scholar
  18. 18.
    Piard J, Holder-Espinasse M, Aral B, Gigot N, Rio M, Tardieu M, et al. Systematic search for neutropenia should be part of the first screening in patients with poikiloderma. Eur J Med Genet. 2012;55:8–11.CrossRefPubMedGoogle Scholar
  19. 19.
    Koparir A, Gezdirici A, Koparir E, Ulucan H, Yilmaz M, Erdemir A, et al. Poikiloderma with neutropenia: genotype-ethnic origin correlation, expanding phenotype and literature review. Am J Med Genet A. 2014;164A:2535–40.CrossRefPubMedGoogle Scholar
  20. 20.
    Kilic SS, Cekic S. Juvenile idiopathic inflammatory myopathy in a patient with dyskeratosis congenita due to C16orf57 mutation. J Pediatr Hematol Oncol. 2016;38(2):e75–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Arnold AW, Itin PH, Pigors M, Kohlhase J, Bruckner-Tuderman L, Has C. Poikiloderma with neutropenia: a novel C16orf57 mutation and clinical diagnostic criteria. Br J Dermatol. 2010;163:866–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Clericuzio C, Harutyunyan K, Jin W, Erickson RP, Irvine AD, McLean WH, et al. Identification of a novel C16orf57 mutation in Athabaskan patients with poikiloderma with neutropenia. Am J Med Genet A. 2011;155A:337–42.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Elisa A. Colombo
    • 1
  • Nursel H. Elcioglu
    • 2
    • 3
  • Claudio Graziano
    • 4
  • Pamela Farinelli
    • 5
  • Elisabetta Di Fede
    • 1
  • Iria Neri
    • 6
  • Elena Facchini
    • 7
  • Mariangela Greco
    • 8
  • Cristina Gervasini
    • 1
  • Lidia Larizza
    • 9
  1. 1.Dipartimento di Scienze della SaluteUniversità degli Studi di MilanoMilanItaly
  2. 2.Department of Pediatric GeneticsMarmara University Medical SchoolIstanbulTurkey
  3. 3.Department of Pediatric GeneticsTurkey and Eastern Mediterranean UniversityMersinTurkey
  4. 4.U.O. Genetica MedicaPoliclinico S. Orsola-MalpighiBolognaItaly
  5. 5.Clinica DermatologicaAzienda ospedaliero universitaria “Maggiore della Carità”NovaraItaly
  6. 6.U.O. DermatologiaPoliclinico S. Orsola-MalpighiBolognaItaly
  7. 7.U.O. Pediatria - Programma di Oncologia, Ematologia e TrapiantoPoliclinico S. Orsola-MalpighiBolognaItaly
  8. 8.Divisione di EmatologiaAzienda Ospedaliero Universitaria “Maggiore della Carità”NovaraItaly
  9. 9.Laboratorio di Citogenetica Medica e Genetica MolecolareCentro di Ricerche e Tecnologie Biomediche IRCCS-Istituto Auxologico ItalianoMilanItaly

Personalised recommendations