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Search: WFRF:(Bryceson Yenan T) > (2015-2019) > Gain-of-function SA...

  • Tesi, BiancaKarolinska Institutet,Karolinska Institute (author)

Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • AMER SOC HEMATOLOGY,2017
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-137087
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-137087URI
  • https://doi.org/10.1182/blood-2016-10-743302DOI
  • https://lup.lub.lu.se/record/87db1fe5-9361-400e-9b49-7c2e7a118883URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:135615633URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies|European Research Council (ERC) under the European Union [311335]; Swedish Research Council; Norwegian Research Council; Swedish Foundation for Strategic Research; Wallenberg Foundation; Swedish Cancer Foundation; Swedish Childhood Cancer Foundation; Stockholm County Council; Karolinska Institutet Center for Innovative Medicine; Hemato-Linne; Cancerfonden; Barncancerfonden; Board of Postgraduate Studies at Karolinska Institute; Swedish Society for Medical Research; Skane University Hospital; Wenner-Gren Foundation; EMBO (ALTF); European Commision [LTFCOFUND] [GA-2013-609409]; Histiocytosis Association; Swedish Society for Medicine; Swedish National Infrastructure for Computing (SNIC) through the Uppsala Multidisciplinary Center for Advanced Computational Science [SNIC b2012204]
  • Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cis SAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34 1 hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-alpha or IFN-gamma induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with 27/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Davidsson, JosefLund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)klin-jed (author)
  • Voss, MatthiasKarolinska Institutet,Karolinska Institute (author)
  • Rahikkala, ElisaUniversity of Oulu, Finland; Oulu University Hospital, Finland (author)
  • Holmes, Tim D.Karolinska University Hospital Huddinge, Sweden; University of Bergen, Norway (author)
  • Chiang, Samuel C. C.Karolinska University Hospital Huddinge, Sweden (author)
  • Komulainen-Ebrahim, JonnaUniversity of Oulu, Finland; Oulu University Hospital, Finland (author)
  • Gorcenco, SorinaLund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk neurogenetik,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Neurogenetics,Lund University Research Groups(Swepub:lu)so1444go (author)
  • Rundberg Nilsson, AlexandraLund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematopoetisk och immunologisk utveckling,Forskargrupper vid Lunds universitet,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,Hematopoietic and immunologic developement,Lund University Research Groups(Swepub:lu)med-aru (author)
  • Ripperger, TimHannover Medical Sch, Germany,Hannover Medical School (author)
  • Kokkonen, HannaleenaOulu University Hospital, Finland (author)
  • Bryder, DavidLund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)med-dbr (author)
  • Fioretos, ThoasLund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)kgen-tfi (author)
  • Henter, Jan-IngeKarolinska Institutet (author)
  • Mottonen, MerjaUniversity of Oulu, Finland; Oulu University Hospital, Finland (author)
  • Niinimaki, RiittaUniversity of Oulu, Finland; Oulu University Hospital, Finland (author)
  • Nilsson, LarsSkåne University Hospital, Sweden (author)
  • Pronk, Cornelis JanLund University, Sweden; Skåne University Hospital, Sweden (author)
  • Puschmann, AndreasLund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Skåne University Hospital(Swepub:lu)med-aps (author)
  • Qian, HongKarolinska Institutet,Karolinska Institute (author)
  • Uusimaa, JohannaUniversity of Oulu, Finland; Oulu University Hospital, Finland (author)
  • Moilanen, JukkaUniversity of Oulu, Finland; Oulu University Hospital, Finland (author)
  • Tedgård, UlfSkåne University Hospital, Sweden(Swepub:lu)pedi-ute (author)
  • Cammenga, JörgLinköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US,Lund University, Sweden,Linköping University Hospital(Swepub:liu)jorca02 (author)
  • Bryceson, Yenan T.Karolinska Institutet,Karolinska Institute (author)
  • Pronk, Kees-JanLund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Hematopoetisk och immunologisk utveckling,Forskargrupper vid Lunds universitet,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine,Hematopoietic and immunologic developement,Lund University Research Groups(Swepub:lu)stem-kpr (author)
  • Karolinska InstitutetKarolinska Institute (creator_code:org_t)

Related titles

  • In:Blood: AMER SOC HEMATOLOGY129:16, s. 2266-22790006-49711528-0020

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