title: Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.
abstract: BACKGROUND
  The Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge-Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified.
  
  
  METHODS
  We performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 persons with the Sturge-Weber syndrome. We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge-Weber syndrome, a port-wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay.
  
  
  RESULTS
  We identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls. The prevalence of the mutant allele in affected tissues ranged from 1.0 to 18.1%. Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Gαq.
  
  
  CONCLUSIONS
  The Sturge-Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ. This finding confirms a long-standing hypothesis. (Funded by the National Institutes of Health and Hunter's Dream for a Cure Foundation.).
authors: Biochemistry, Cellular and Molecular Biology Program, Johns Hopkins School of Medicine, and Department of Neurology and Developmental Medicine, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
authors: Matthew D
authors: MD
authors: Shirley
authors: Hao
authors: H
authors: Tang
authors: Carol J
authors: CJ
authors: Gallione
authors: Joseph D
authors: JD
authors: Baugher
authors: Laurence P
authors: LP
authors: Frelin
authors: Bernard
authors: B
authors: Cohen
authors: Paula E
authors: PE
authors: North
authors: Douglas A
authors: DA
authors: Marchuk
authors: Anne M
authors: AM
authors: Comi
authors: Jonathan
authors: J
authors: Pevsner
mesh_terms: D001921:Brain / Q000473:pathology; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D019339:Port-Wine Stain / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013341:Sturge-Weber Syndrome / Q000235:genetics*
chemical_list: C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
references: Heart Vessels. 1997;12(6):300-5
references: 9860198
references: J Am Acad Dermatol. 1987 Apr;16(4):899-906
references: 3033033
references: J Biol Chem. 1992 Jan 5;267(1):31-4
references: 1309740
references: Lymphat Res Biol. 2007;5(4):233-6
references: 18370913
references: Science. 1994 Sep 2;265(5177):1405-12
references: 8073283
references: N Engl J Med. 1991 Dec 12;325(24):1688-95
references: 1944469
references: J Biol Chem. 2004 Nov 12;279(46):47438-45
references: 15339913
references: Cell. 2012 Jul 20;150(2):251-63
references: 22817889
references: Arch Ophthalmol. 2011 Jun;129(6):746-50
references: 21670341
references: Lymphat Res Biol. 2007;5(4):257-64
references: 18370916
references: Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):428-32
references: 9012799
references: Genome Res. 2011 Sep;21(9):1529-42
references: 21700766
references: N Engl J Med. 2010 Dec 2;363(23):2191-9
references: 21083380
references: Cell. 1996 Aug 9;86(3):445-52
references: 8756726
references: Nature. 2009 Jan 29;457(7229):599-602
references: 19078957
references: Pediatr Dermatol. 2012 Jan-Feb;29(1):32-7
references: 21906147
references: J Craniofac Surg. 2009 Mar;20 Suppl 1:617-21
references: 19182685
references: Mol Cell. 2013 Jan 10;49(1):94-108
references: 23177739
references: J Plast Reconstr Aesthet Surg. 2008 Aug;61(8):889-93
references: 17604243
references: N Engl J Med. 2011 Aug 18;365(7):611-9
references: 21793738
references: Pharmacol Rev. 2011 Sep;63(3):728-49
references: 21737532
references: Eur J Dermatol. 2003 May-Jun;13(3):238-41
references: 12804981
references: J Craniofac Surg. 2001 Sep;12(5):485-9
references: 11572256
references: Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7179-84
references: 19369209
references: Nat Genet. 2004 Sep;36(9):961-8
references: 15322542
references: Pediatr Dermatol. 2004 Nov-Dec;21(6):642-5
references: 15575847