Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex

Lisbeth Birk Møller, Bitten Schönewolf-Greulich, Thomas Rosengren, Lasse Jonsgaard Larsen, John R. Østergaard, Mette Sommerlund, Caroline Ostenfeldt, Brian Stausbøl-Grøn, Karen Markussen Linnet, Pernille Axél Gregersen, Uffe Birk Jensen

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Resumé

    TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1838Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the “silent” c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.
    OriginalsprogEngelsk
    TidsskriftMolecular Genetics and Metabolism
    Vol/bind120
    Udgave nummer4
    Sider (fra-til)384-391
    ISSN1096-7192
    DOI
    StatusUdgivet - 2017

    Emneord

    • Hypomelanotic macules
    • mTOR
    • Silent substitution
    • TSC
    • TSC2

    Citer dette

    Møller, L. B., Schönewolf-Greulich, B., Rosengren, T., Larsen, L. J., Østergaard, J. R., Sommerlund, M., ... Jensen, U. B. (2017). Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex. Molecular Genetics and Metabolism, 120(4), 384-391. https://doi.org/10.1016/j.ymgme.2017.02.008
    Møller, Lisbeth Birk ; Schönewolf-Greulich, Bitten ; Rosengren, Thomas ; Larsen, Lasse Jonsgaard ; Østergaard, John R. ; Sommerlund, Mette ; Ostenfeldt, Caroline ; Stausbøl-Grøn, Brian ; Linnet, Karen Markussen ; Gregersen, Pernille Axél ; Jensen, Uffe Birk. / Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex. I: Molecular Genetics and Metabolism. 2017 ; Bind 120, Nr. 4. s. 384-391.
    @article{a574c632907048ad9e3705649e085762,
    title = "Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex",
    abstract = "TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1838Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the “silent” c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.",
    keywords = "Hypomelanotic macules, mTOR, Silent substitution, TSC, TSC2, Hypomelanotic macules, mTOR, Silent substitution, TSC, TSC2",
    author = "M{\o}ller, {Lisbeth Birk} and Bitten Sch{\"o}newolf-Greulich and Thomas Rosengren and Larsen, {Lasse Jonsgaard} and {\O}stergaard, {John R.} and Mette Sommerlund and Caroline Ostenfeldt and Brian Stausb{\o}l-Gr{\o}n and Linnet, {Karen Markussen} and Gregersen, {Pernille Ax{\'e}l} and Jensen, {Uffe Birk}",
    year = "2017",
    doi = "10.1016/j.ymgme.2017.02.008",
    language = "English",
    volume = "120",
    pages = "384--391",
    journal = "Molecular Genetics and Metabolism",
    issn = "1096-7192",
    publisher = "Academic Press",
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    Møller, LB, Schönewolf-Greulich, B, Rosengren, T, Larsen, LJ, Østergaard, JR, Sommerlund, M, Ostenfeldt, C, Stausbøl-Grøn, B, Linnet, KM, Gregersen, PA & Jensen, UB 2017, 'Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex', Molecular Genetics and Metabolism, bind 120, nr. 4, s. 384-391. https://doi.org/10.1016/j.ymgme.2017.02.008

    Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex. / Møller, Lisbeth Birk; Schönewolf-Greulich, Bitten; Rosengren, Thomas; Larsen, Lasse Jonsgaard; Østergaard, John R.; Sommerlund, Mette; Ostenfeldt, Caroline; Stausbøl-Grøn, Brian; Linnet, Karen Markussen; Gregersen, Pernille Axél; Jensen, Uffe Birk.

    I: Molecular Genetics and Metabolism, Bind 120, Nr. 4, 2017, s. 384-391.

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    TY - JOUR

    T1 - Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex

    AU - Møller, Lisbeth Birk

    AU - Schönewolf-Greulich, Bitten

    AU - Rosengren, Thomas

    AU - Larsen, Lasse Jonsgaard

    AU - Østergaard, John R.

    AU - Sommerlund, Mette

    AU - Ostenfeldt, Caroline

    AU - Stausbøl-Grøn, Brian

    AU - Linnet, Karen Markussen

    AU - Gregersen, Pernille Axél

    AU - Jensen, Uffe Birk

    PY - 2017

    Y1 - 2017

    N2 - TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1838Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the “silent” c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.

    AB - TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1838Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the “silent” c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.

    KW - Hypomelanotic macules

    KW - mTOR

    KW - Silent substitution

    KW - TSC

    KW - TSC2

    KW - Hypomelanotic macules

    KW - mTOR

    KW - Silent substitution

    KW - TSC

    KW - TSC2

    UR - https://doi.org/10.1016/j.ymgme.2017.11.007

    U2 - 10.1016/j.ymgme.2017.02.008

    DO - 10.1016/j.ymgme.2017.02.008

    M3 - Journal article

    VL - 120

    SP - 384

    EP - 391

    JO - Molecular Genetics and Metabolism

    JF - Molecular Genetics and Metabolism

    SN - 1096-7192

    IS - 4

    ER -