PMID- 31053780
OWN - NLM
STAT- MEDLINE
DCOM- 20200612
LR  - 20211204
IS  - 1476-5438 (Electronic)
IS  - 1018-4813 (Print)
IS  - 1018-4813 (Linking)
VI  - 27
IP  - 9
DP  - 2019 Sep
TI  - A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore 
      syndrome and Antiphospholipid syndrome.
PG  - 1369-1378
LID - 10.1038/s41431-019-0418-1 [doi]
AB  - We report the clinical, biochemical and genetic findings from a Spanish girl of 
      Caucasian origin who presented with macrocephaly, dysmorphic facial features, 
      developmental delay, hypotonia, combined oxidative phosphorylation (OxPhos) 
      deficiency, epilepsy and anti-phospholipid antibodies (aPL). Whole-exome 
      sequencing (WES) uncovered a heterozygous variant in the MTOR gene (NM_004958.3: 
      c.7235A>T: p.(Asp2412Val)) that encodes for the Serine/threonine-protein kinase 
      mTOR. The substrates phosphorylation experiments demonstrated that this variant 
      exerts its effect by gain-of-function (GOF) and autosomal dominant mechanism. GOF 
      variants in this protein have been associated with Smith-Kingsmore syndrome 
      (SKS), a rare autosomal dominant disorder characterized by intellectual 
      disability, macrocephaly, seizure, developmental delay and dysmorphic facial 
      features. Furthermore, the mTOR pathway has been demonstrated previously to be 
      involved in many types of endothelium injuries including the antiphospholipid 
      syndrome (APS), a systemic autoimmune disease characterized by the production of 
      aPL with recurrent vascular thrombosis. Therefore, our patient is the first one 
      with an mTOR variant and diagnosed with SKS and APS. In conclusion, our data 
      expand both the genetic and phenotypic spectrum associated with MTOR gene 
      variants.
FAU - Rodriguez-Garcia, Maria Elena
AU  - Rodriguez-Garcia ME
AD  - Laboratorio de Enfermedades Mitocondriales. Instituto de Investigacion Hospital 
      12 de Octubre (i+12), E-28041, Madrid, Spain.
FAU - Cotrina-Vinagre, Francisco Javier
AU  - Cotrina-Vinagre FJ
AD  - Laboratorio de Enfermedades Mitocondriales. Instituto de Investigacion Hospital 
      12 de Octubre (i+12), E-28041, Madrid, Spain.
FAU - Bellusci, Marcello
AU  - Bellusci M
AD  - Unidad Pediatrica de Enfermedades Raras, Enfermedades Mitocondriales y 
      Metabolicas Hereditarias, Hospital 12 de Octubre, E-28041, Madrid, Spain.
FAU - Martinez de Aragon, Ana
AU  - Martinez de Aragon A
AD  - Unidad Pediatrica de Neurorradiologia, Hospital 12 de Octubre, E-28041, Madrid, 
      Spain.
FAU - Hernandez-Sanchez, Laura
AU  - Hernandez-Sanchez L
AD  - Laboratorio de Enfermedades Mitocondriales. Instituto de Investigacion Hospital 
      12 de Octubre (i+12), E-28041, Madrid, Spain.
FAU - Carnicero-Rodriguez, Patricia
AU  - Carnicero-Rodriguez P
AD  - Laboratorio de Enfermedades Mitocondriales. Instituto de Investigacion Hospital 
      12 de Octubre (i+12), E-28041, Madrid, Spain.
FAU - Martin-Hernandez, Elena
AU  - Martin-Hernandez E
AD  - Unidad Pediatrica de Enfermedades Raras, Enfermedades Mitocondriales y 
      Metabolicas Hereditarias, Hospital 12 de Octubre, E-28041, Madrid, Spain.
FAU - Martinez-Azorin, Francisco
AU  - Martinez-Azorin F
AUID- ORCID: 0000-0001-6250-7745
AD  - Laboratorio de Enfermedades Mitocondriales. Instituto de Investigacion Hospital 
      12 de Octubre (i+12), E-28041, Madrid, Spain. fmartinez@h12o.es.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), U723, 
      E-28041, Madrid, Spain. fmartinez@h12o.es.
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190503
PL  - England
TA  - Eur J Hum Genet
JT  - European journal of human genetics : EJHG
JID - 9302235
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Alleles
MH  - Amino Acid Substitution
MH  - Antiphospholipid Syndrome/*diagnosis/*genetics/metabolism
MH  - Brain/abnormalities/diagnostic imaging
MH  - Child, Preschool
MH  - Comparative Genomic Hybridization
MH  - Electron Transport
MH  - Female
MH  - *Gain of Function Mutation
MH  - *Genes, Dominant
MH  - Genotype
MH  - Humans
MH  - Karyotyping
MH  - Magnetic Resonance Imaging
MH  - Mitochondria, Muscle/genetics/metabolism
MH  - Neurodevelopmental Disorders/*diagnosis/*genetics/metabolism
MH  - Pedigree
MH  - Phenotype
MH  - Signal Transduction
MH  - Syndrome
MH  - TOR Serine-Threonine Kinases/*genetics
PMC - PMC6777539
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/05/06 06:00
MHDA- 2020/06/13 06:00
PMCR- 2020/09/01
CRDT- 2019/05/05 06:00
PHST- 2018/11/22 00:00 [received]
PHST- 2019/04/16 00:00 [accepted]
PHST- 2019/03/21 00:00 [revised]
PHST- 2019/05/06 06:00 [pubmed]
PHST- 2020/06/13 06:00 [medline]
PHST- 2019/05/05 06:00 [entrez]
PHST- 2020/09/01 00:00 [pmc-release]
AID - 10.1038/s41431-019-0418-1 [pii]
AID - 418 [pii]
AID - 10.1038/s41431-019-0418-1 [doi]
PST - ppublish
SO  - Eur J Hum Genet. 2019 Sep;27(9):1369-1378. doi: 10.1038/s41431-019-0418-1. Epub 
      2019 May 3.