Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex.
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.(Ser1383Ser), 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.
Applied Human Molecular Genetics, Clinical Genetics Clinic, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark; Department of Science and Environment, Roskilde University, Roskilde, Denmark. Electronic address: Lisbeth.Birk.Moeller@regionh.dk.
Lisbeth Birk
LB
Møller
Applied Human Molecular Genetics, Clinical Genetics Clinic, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
Bitten
B
Schönewolf-Greulich
Applied Human Molecular Genetics, Clinical Genetics Clinic, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
Thomas
T
Rosengren
Applied Human Molecular Genetics, Clinical Genetics Clinic, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
Lasse Jonsgaard
LJ
Larsen
Centre for Rare Disorders, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
John R
JR
Ostergaard
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.
Mette
M
Sommerlund
Applied Human Molecular Genetics, Clinical Genetics Clinic, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
Caroline
C
Ostenfeldt
Department of Radiology/MR Centre, Aarhus University Hospital, Aarhus, Denmark.
Brian
B
Stausbøl-Grøn
Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.
Karen Markussen
KM
Linnet
Centre for Rare Disorders, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Pernille Axél
PA
Gregersen
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Uffe Birk
UB
Jensen
D019943:Amino Acid Substitution; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D012326:RNA Splicing; D017422:Sequence Analysis, DNA; D012871:Skin Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000150:complications* / Q000235:genetics; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D046912:Multiprotein Complexes; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
Hypomelanotic macules; Silent substitution; TSC; TSC2; mTOR