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Gain-of-function SA...
Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms
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- Tesi, Bianca (author)
- Karolinska Institutet,Karolinska Institute
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- 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
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- Voss, Matthias (author)
- Karolinska Institutet,Karolinska Institute
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- Rahikkala, Elisa (author)
- University of Oulu, Finland; Oulu University Hospital, Finland
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- Holmes, Tim D. (author)
- Karolinska University Hospital Huddinge, Sweden; University of Bergen, Norway
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- Chiang, Samuel C. C. (author)
- Karolinska University Hospital Huddinge, Sweden
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- Komulainen-Ebrahim, Jonna (author)
- University of Oulu, Finland; Oulu University Hospital, Finland
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- 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
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- 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
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- Ripperger, Tim (author)
- Hannover Medical Sch, Germany,Hannover Medical School
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- Kokkonen, Hannaleena (author)
- Oulu University Hospital, Finland
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- 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
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- 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
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- Henter, Jan-Inge (author)
- Karolinska Institutet
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- Mottonen, Merja (author)
- University of Oulu, Finland; Oulu University Hospital, Finland
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- Niinimaki, Riitta (author)
- University of Oulu, Finland; Oulu University Hospital, Finland
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- Nilsson, Lars (author)
- Skåne University Hospital, Sweden
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- Pronk, Cornelis Jan (author)
- Lund University, Sweden; Skåne University Hospital, Sweden
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- 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
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- Qian, Hong (author)
- Karolinska Institutet,Karolinska Institute
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- Uusimaa, Johanna (author)
- University of Oulu, Finland; Oulu University Hospital, Finland
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- Moilanen, Jukka (author)
- University of Oulu, Finland; Oulu University Hospital, Finland
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- Tedgård, Ulf (author)
- Skåne University Hospital, Sweden
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- Cammenga, Jörg (author)
- Linköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US,Lund University, Sweden,Linköping University Hospital
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- Bryceson, Yenan T. (author)
- Karolinska Institutet,Karolinska Institute
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- 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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(creator_code:org_t)
- AMER SOC HEMATOLOGY, 2017
- 2017
- English.
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In: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 129:16, s. 2266-2279
- Related links:
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https://ashpublicati...
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http://dx.doi.org/10...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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Abstract
Subject headings
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- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Keyword
- Journal Article
Publication and Content Type
- ref (subject category)
- art (subject category)
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Blood
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To the university's database
- By the author/editor
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Tesi, Bianca
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Davidsson, Josef
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Voss, Matthias
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Rahikkala, Elisa
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Holmes, Tim D.
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Chiang, Samuel C ...
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show more...
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Komulainen-Ebrah ...
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Gorcenco, Sorina
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Rundberg Nilsson ...
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Ripperger, Tim
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Kokkonen, Hannal ...
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Bryder, David
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Fioretos, Thoas
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Henter, Jan-Inge
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Mottonen, Merja
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Niinimaki, Riitt ...
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Nilsson, Lars
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Pronk, Cornelis ...
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Puschmann, Andre ...
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Qian, Hong
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Uusimaa, Johanna
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Moilanen, Jukka
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Tedgård, Ulf
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Cammenga, Jörg
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Bryceson, Yenan ...
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Pronk, Kees-Jan
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Blood
- By the university
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Linköping University
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Lund University
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Karolinska Institutet