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 - Silent substitution
KW - TSC
KW - TSC2
KW - mTOR
KW - Hypomelanotic macules
KW - Silent substitution
KW - TSC
KW - TSC2
KW - mTOR
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
SN - 1096-7192
VL - 120
SP - 384
EP - 391
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -