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

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

Tesi, Bianca (author): Karolinska Institutet,Karolinska Institute

Davidsson, Josef (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

Voss, Matthias (author): Karolinska Institutet,Karolinska Institute

Rahikkala, Elisa (author): University of Oulu, Finland; Oulu University Hospital, Finland

Holmes, Tim D. (author): Karolinska University Hospital Huddinge, Sweden; University of Bergen, Norway

Chiang, Samuel C. C. (author): Karolinska University Hospital Huddinge, Sweden

Komulainen-Ebrahim, Jonna (author): University of Oulu, Finland; Oulu University Hospital, Finland

Gorcenco, Sorina (author): Lund 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

Rundberg Nilsson, Alexandra (author): Lund 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

Ripperger, Tim (author): Hannover Medical Sch, Germany,Hannover Medical School

Kokkonen, Hannaleena (author): Oulu University Hospital, Finland

Bryder, David (author): Lund University,Lunds universitet,Avdelningen för molekylär hematologi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Hematology (DMH),Department of Laboratory Medicine,Faculty of Medicine

Fioretos, Thoas (author): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine

Henter, Jan-Inge (author): Karolinska Institutet

Mottonen, Merja (author): University of Oulu, Finland; Oulu University Hospital, Finland

Niinimaki, Riitta (author): University of Oulu, Finland; Oulu University Hospital, Finland

Nilsson, Lars (author): Skåne University Hospital, Sweden

Pronk, Cornelis Jan (author): Lund University, Sweden; Skåne University Hospital, Sweden

Puschmann, Andreas (author): Lund 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

Qian, Hong (author): Karolinska Institutet,Karolinska Institute

Uusimaa, Johanna (author): University of Oulu, Finland; Oulu University Hospital, Finland

Moilanen, Jukka (author): University of Oulu, Finland; Oulu University Hospital, Finland

Tedgård, Ulf (author): Skåne University Hospital, Sweden

Cammenga, Jörg (author): Linköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US,Lund University, Sweden,Linköping University Hospital

Bryceson, Yenan T. (author): Karolinska Institutet,Karolinska Institute

Pronk, Kees-Jan (author): Lund 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

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AMER SOC HEMATOLOGY, 2017
2017
English.
In: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 129:16, s. 2266-2279

Related links:: https://ashpublicati...; show more...; http://dx.doi.org/10...; https://urn.kb.se/re...; https://doi.org/10.1...; https://lup.lub.lu.s...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

Articles in the publication: Blood

By the university: Linköping University; Lund University; Karolinska Institutet

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

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