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Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms
Karolinska University Hospital Huddinge, Sweden; Karolinska Institute, Sweden.
Lund University, Sweden; Skåne University Hospital, Sweden.
Karolinska University Hospital Huddinge, Sweden.
University of Oulu, Finland; Oulu University Hospital, Finland.
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2017 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 129, no 16, 2266-2279 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY , 2017. Vol. 129, no 16, 2266-2279 p.
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Hematology
Identifiers
URN: urn:nbn:se:liu:diva-137087DOI: 10.1182/blood-2016-10-743302ISI: 000399565300012PubMedID: 28202457OAI: oai:DiVA.org:liu-137087DiVA: diva2:1093275
Note

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]

Available from: 2017-05-05 Created: 2017-05-05 Last updated: 2017-05-23

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Cammenga, Jörg
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of Haematology
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CiteExportLink to record
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Citation style
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