John Rosendahl Østergaard

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

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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; Ostergaard, John R; Sommerlund, Mette; Ostenfeldt, Caroline; Stausbøl-Grøn, Brian; Linnet, Karen Markussen; Gregersen, Pernille Axél; Jensen, Uffe Birk.

In: Molecular Genetics and Metabolism, Vol. 120, No. 4, 04.2017, p. 384-391.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Møller, LB, Schönewolf-Greulich, B, Rosengren, T, Larsen, LJ, Ostergaard, 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, vol. 120, no. 4, pp. 384-391. https://doi.org/10.1016/j.ymgme.2017.02.008

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Vancouver

Møller LB, Schönewolf-Greulich B, Rosengren T, Larsen LJ, Ostergaard JR, Sommerlund M et al. Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex. Molecular Genetics and Metabolism. 2017 Apr;120(4):384-391. https://doi.org/10.1016/j.ymgme.2017.02.008

Author

Møller, Lisbeth Birk ; Schönewolf-Greulich, Bitten ; Rosengren, Thomas ; Larsen, Lasse Jonsgaard ; Ostergaard, 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. In: Molecular Genetics and Metabolism. 2017 ; Vol. 120, No. 4. pp. 384-391.

Bibtex

@article{11e11622690842e8a2f5d3741185c7b8,
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 = "Journal Article",
author = "M{\o}ller, {Lisbeth Birk} and Bitten Sch{\"o}newolf-Greulich and Thomas Rosengren and Larsen, {Lasse Jonsgaard} and Ostergaard, {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}",
note = "Copyright {\textcopyright} 2017 Elsevier Inc. All rights reserved.",
year = "2017",
month = apr,
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",
number = "4",

}

RIS

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 - Ostergaard, John R

AU - Sommerlund, Mette

AU - Ostenfeldt, Caroline

AU - Stausbøl-Grøn, Brian

AU - Linnet, Karen Markussen

AU - Gregersen, Pernille Axél

AU - Jensen, Uffe Birk

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/4

Y1 - 2017/4

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 - Journal Article

U2 - 10.1016/j.ymgme.2017.02.008

DO - 10.1016/j.ymgme.2017.02.008

M3 - Journal article

C2 - 28336152

VL - 120

SP - 384

EP - 391

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 4

ER -