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  • 1.
    Gunnarsson, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hellström, Anders R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tixier-Boichard, Michele
    Minvielle, Francis
    Bed'hom, Bertrand
    Ito, Shin'ichi
    Jensen, Per
    Rattink, Annemieke
    Vereijken, Addie
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail2007Ingår i: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 175, nr 2, s. 867-877Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    S*S (Silver), S*N (wild type/gold), and S*AL (sex-linked imperfect albinism) form a series of alleles at the S (Silver) locus on chicken (Gallus gallus) chromosome Z. Similarly, sex-linked imperfect albinism (AL*A) is the bottom recessive allele at the orthologous AL locus in Japanese quail (Coturnix japonica). The solute carrier family 45, member 2, protein (SLC45A2), previously denoted membrane-associated transporter protein (MATP), has an important role in vesicle sorting in the melanocytes. Here we report five SLC45A2 mutations. The 106delT mutation in the chicken S*AL allele results in a frameshift and a premature stop codon and the corresponding mRNA appears to be degraded by nonsense-mediated mRNA decay. A splice-site mutation in the Japanese quail AL*A allele causes in-frame skipping of exon 4. Two independent missense mutations (Tyr277Cys and Leu347Met) were associated with the Silver allele in chicken. The functional significance of the former mutation, associated only with Silver in White Leghorn, is unclear. Ala72Asp was associated with the cinnamon allele (AL*C) in the Japanese quail. The most interesting feature concerning the SLC45A2 variants documented in this study is the specific inhibition of expression of red pheomelanin in Silver chickens. This phenotypic effect cannot be explained on the basis of the current, incomplete, understanding of SLC45A2 function. It is an enigma why recessive null mutations at this locus cause an almost complete absence of both eumelanin and pheomelanin whereas some missense mutations are dominant and cause a specific inhibition of pheomelanin production.

  • 2.
    Hellström, Anders R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten.
    Dissecting Phenotypic Variation in Pigmentation using Forward and Reverse Genetics2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Coat color and patterning phenotypes have been extensively studied as a model for advancing our understanding of the relationship between genetic and phenotypic variation. In this thesis, genes of relevance for pigment cell biology were investigated. The dissertation is divided in two parts. Forward genetics was used in the first part (Paper I and II) to identify the genes controlling the Silver and Sex-linked barring loci in chicken. In the second part, reverse genetics was employed to create a mouse line in which the PMEL17 protein is inactivated (Paper III).

    In Paper I, we report five mutations in SLC45A2 causing plumage color variants in both chicken and Japanese quail. Normal function of the SLC45A2 gene has previously been shown to be essential for the synthesis of both red/yellow pigment (pheomelanin) and brown/black pigment (eumelanin) in numerous species, including humans. The major discovery in this paper is the specific inhibition of pheomelanin in Silver chickens, whilst null mutations at this locus cause an almost complete absence of both pheomelanin and eumelanin.

    In Paper II, we report that Sex-linked barring in chickens is controlled by the CDKN2A/B tumor suppressor locus. The locus encodes two proteins, INK4B and ARF. The genetic analysis indicates that missense mutations in ARF or mutations in the promoter region of the ARF transcript are causing Sex-linked barring. In previous studies, mutations inactivating the CDKN2A/B tumor suppressor locus, have been shown to be responsible for familiar forms of human melanoma. Here we propose that these mutations in chicken CDKN2A/B cause the premature cell death of melanocytes as opposed to the cell proliferation and tumor growth associated with loss-of-function alleles in humans.

    In Paper III, we created a mouse line in which the PMEL17 protein is inactivated. Missense mutations in the gene encoding PMEL17 have previously been shown to be associated with reduced levels of eumelanin in epidermal tissues in several vertebrate species. The knockout mice are viable, fertile, and display no obvious developmental defects. The eumelanosomes within the melanocytes of these mice are spherical in contrast to the cigar-like shaped eumelanosomes present in wild-type animals. PMEL17 protein inactivation has only a subtle diluting effect on the coat color phenotype in four different genetic backgrounds. This suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations.

    Delarbeten
    1. Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail
    Öppna denna publikation i ny flik eller fönster >>Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail
    Visa övriga...
    2007 (Engelska)Ingår i: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 175, nr 2, s. 867-877Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    S*S (Silver), S*N (wild type/gold), and S*AL (sex-linked imperfect albinism) form a series of alleles at the S (Silver) locus on chicken (Gallus gallus) chromosome Z. Similarly, sex-linked imperfect albinism (AL*A) is the bottom recessive allele at the orthologous AL locus in Japanese quail (Coturnix japonica). The solute carrier family 45, member 2, protein (SLC45A2), previously denoted membrane-associated transporter protein (MATP), has an important role in vesicle sorting in the melanocytes. Here we report five SLC45A2 mutations. The 106delT mutation in the chicken S*AL allele results in a frameshift and a premature stop codon and the corresponding mRNA appears to be degraded by nonsense-mediated mRNA decay. A splice-site mutation in the Japanese quail AL*A allele causes in-frame skipping of exon 4. Two independent missense mutations (Tyr277Cys and Leu347Met) were associated with the Silver allele in chicken. The functional significance of the former mutation, associated only with Silver in White Leghorn, is unclear. Ala72Asp was associated with the cinnamon allele (AL*C) in the Japanese quail. The most interesting feature concerning the SLC45A2 variants documented in this study is the specific inhibition of expression of red pheomelanin in Silver chickens. This phenotypic effect cannot be explained on the basis of the current, incomplete, understanding of SLC45A2 function. It is an enigma why recessive null mutations at this locus cause an almost complete absence of both eumelanin and pheomelanin whereas some missense mutations are dominant and cause a specific inhibition of pheomelanin production.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-22448 (URN)10.1534/genetics.106.063107 (DOI)000244689600037 ()17151254 (PubMedID)
    Tillgänglig från: 2008-03-05 Skapad: 2008-03-05 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    2. Sex-linked barring in chickens is controlled by the CDKN2A/B tumour suppressor locus
    Öppna denna publikation i ny flik eller fönster >>Sex-linked barring in chickens is controlled by the CDKN2A/B tumour suppressor locus
    Visa övriga...
    2010 (Engelska)Ingår i: Pigment Cell and Melanoma Research, ISSN 1755-1471, Vol. 23, nr 4, s. 521-530Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Sex-linked barring, a common plumage colour found in chickens, is characterized by black and white barred feathers. Previous studies have indicated that the white bands are caused by an absence of melanocytes in the feather follicle during the growth of this region. Here we show that Sex-linked barring is controlled by the CDKN2A/B locus, which encodes the INK4b and ARF transcripts. We identified two non-coding mutations in CDKN2A that showed near complete association with the phenotype. Also identified were two missense mutations at highly conserved sites, V9D and R10C, and every bird tested with a confirmed Sex-linked barring phenotype carried one of these missense mutations. Further work is required to determine if one of these or a combined effect of two or more CDKN2A mutations is causing Sex-linked barring. This novel finding provides the first evidence that the tumour suppressor locus CDKN2A/B can affect pigmentation phenotypes and sheds new light on the functional significance of this gene.

    Nyckelord
    INK4b, ARF, CDKN2, sex-linked barring, chicken, melanogenesis, melanocytes
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-124942 (URN)10.1111/j.1755-148X.2010.00700.x (DOI)000280711100009 ()20374521 (PubMedID)
    Tillgänglig från: 2010-05-06 Skapad: 2010-05-06 Senast uppdaterad: 2011-02-24Bibliografiskt granskad
    3. Inactivation of the Silver gene alters the shape of eumelanosomes but has only a subtle effect on pigmentation
    Öppna denna publikation i ny flik eller fönster >>Inactivation of the Silver gene alters the shape of eumelanosomes but has only a subtle effect on pigmentation
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-131301 (URN)
    Tillgänglig från: 2010-09-29 Skapad: 2010-09-29 Senast uppdaterad: 2012-02-24
  • 3.
    Hellström, Anders R.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sundström, Elisabeth
    Gunnarsson, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bed'hom, Bertrand
    Tixier-Boichard, Michele
    Honaker, Christa F.
    Sahlqvist, Anna-Stina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Jensen, Per
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Siegel, Paul B.
    Kerje, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sex-linked barring in chickens is controlled by the CDKN2A/B tumour suppressor locus2010Ingår i: Pigment Cell and Melanoma Research, ISSN 1755-1471, Vol. 23, nr 4, s. 521-530Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sex-linked barring, a common plumage colour found in chickens, is characterized by black and white barred feathers. Previous studies have indicated that the white bands are caused by an absence of melanocytes in the feather follicle during the growth of this region. Here we show that Sex-linked barring is controlled by the CDKN2A/B locus, which encodes the INK4b and ARF transcripts. We identified two non-coding mutations in CDKN2A that showed near complete association with the phenotype. Also identified were two missense mutations at highly conserved sites, V9D and R10C, and every bird tested with a confirmed Sex-linked barring phenotype carried one of these missense mutations. Further work is required to determine if one of these or a combined effect of two or more CDKN2A mutations is causing Sex-linked barring. This novel finding provides the first evidence that the tumour suppressor locus CDKN2A/B can affect pigmentation phenotypes and sheds new light on the functional significance of this gene.

  • 4.
    Hellström, Anders R.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Watt, Brenda
    Fard, Shahrzad Shirazi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Tenza, Daniele
    Mannström, Paula
    Narfström, Kristina
    Ekesten, Björn
    Ito, Shosuke
    Wakamatsu, Kazumasa
    Larsson, Jimmy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Ulfendahl, Mats
    Kullander, Klas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Raposo, Graca
    Kerje, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hallböök, Finn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Marks, Michael S.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Inactivation of Pmel Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation2011Ingår i: PLoS Genetics, ISSN 1553-7390, Vol. 7, nr 9, s. e1002285-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel(-/-)). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel(-/-) melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.

  • 5.
    Pandzic, Tatjana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Larsson, Jimmy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kundu, Snehangshu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ban, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. NUS, Yong Loo Lin Sch Med, A STAR, Dept Biochem,Inst Mol & Cell Biol, Singapore, Singapore..
    Ali, Muhammad Akhtar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hellström, Anders R.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Schuh, Anna
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Clifford, Ruth
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Blakemore, Stuart J.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Strefford, Jonathan C.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Baumann, Tycho
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Lopez-Guillermo, Armando
    Hosp Clin Barcelona, IDIBAPS, Serv Hematol, Barcelona, Spain..
    Campo, Elias
    Univ Barcelona, IDIBAPS, Hosp Clin, Unitat Hematol, Barcelona, Spain..
    Ljungström, Viktor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hellström, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia2016Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 24, s. 6217-6227Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Experimental Design: We used piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. Conclusions: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy.

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