title: Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12.
abstract: The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C>G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.
authors: 1] Department of cardiovascular sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium [2] Department of Pediatrics, UZ Leuven, Leuven, Belgium.
authors: Christophe
authors: C
authors: Goubau
authors: Koen
authors: K
authors: Devriendt
authors: Nathalie
authors: N
authors: Van der Aa
authors: An
authors: A
authors: Crepel
authors: Dagmar
authors: D
authors: Wieczorek
authors: Tjitske
authors: T
authors: Kleefstra
authors: Marjolein H
authors: MH
authors: Willemsen
authors: Anita
authors: A
authors: Rauch
authors: Andreas
authors: A
authors: Tzschach
authors: Thomy
authors: T
authors: de Ravel
authors: Peter
authors: P
authors: Leemans
authors: Chris
authors: C
authors: Van Geet
authors: Gunnar
authors: G
authors: Buyse
authors: Kathleen
authors: K
authors: Freson
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002648:Child; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins
references: Dev Cell. 2009 Apr;16(4):576-87
references: 19386266
references: Neuron. 2012 Jun 21;74(6):1045-58
references: 22726835
references: Neurology. 2011 May 3;76(18):1600-2
references: 21536641
references: J Neurobiol. 1994 Oct;25(10):1293-309
references: 7815060
references: Blood. 2009 Dec 24;114(27):5532-40
references: 19801445
references: Development. 2006 May;133(9):1831-44
references: 16613831
references: Am J Med Genet A. 2011 Oct;155A(10):2584-8
references: 21910242
references: Eur J Hum Genet. 2009 Dec;17(12):1577-81
references: 19623215
references: Blood. 2005 Oct 1;106(7):2356-62
references: 15956286
references: Neurogenetics. 2010 May;11(2):241-9
references: 19806373
references: J Neurosci. 2007 Oct 10;27(41):11103-11
references: 17928452
references: Ann Neurol. 2010 Dec;68(6):944-50
references: 21154482
references: Nat Cell Biol. 2009 May;11(5):545-56
references: 19329994
references: J Neurosci. 2011 Jan 12;31(2):402-13
references: 21228151
references: Brief Funct Genomic Proteomic. 2009 Jul;8(4):317-32
references: 19596743
references: Genomics. 1994 Jun;21(3):551-7
references: 7959731
references: J Neurosci. 2012 Feb 22;32(8):2846-55
references: 22357867
references: Am J Med Genet. 2001 Aug 1;102(2):173-82
references: 11477612
references: Nat Neurosci. 2006 Jun;9(6):743-51
references: 16680166
references: Am J Hum Genet. 2008 Jul;83(1):89-93
references: 18571142
references: Eur J Med Genet. 2009 Nov-Dec;52(6):440-2
references: 19772934
references: Neuroscience. 2007 Aug 24;148(2):385-99
references: 17640820
references: Eur J Hum Genet. 2013 May;21(5):522-7
references: 22968132
references: Am J Med Genet A. 2006 Oct 15;140(20):2180-7
references: 16955412
references: Hum Genet. 2005 Oct;117(6):536-44
references: 16133170
references: J Med Genet. 2011 Jun;48(6):396-406
references: 21441262
references: Eur J Med Genet. 2012 Nov;55(11):586-98
references: 22796527
references: Hum Mol Genet. 2003 May 15;12(10):1121-30
references: 12719376
references: Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2232-40
references: 22814751
references: J Med Genet. 2012 Jun;49(6):366-72
references: 22636604
references: Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1874-82
references: 19661482
references: J Clin Invest. 2004 Mar;113(6):905-12
references: 15067323
references: Eur J Hum Genet. 2012 Jun;20(6):595-6; author reply 596-7
references: 22258524
references: Eur J Hum Genet. 2011 Jan;19(1):102-7
references: 20736978
references: Science. 2004 Jan 2;303(5654):56-9
references: 14704420
references: Eur J Med Genet. 2009 Mar-Jun;52(2-3):148-52
references: 19303466
references: Am J Hum Genet. 2007 Feb;80(2):232-40
references: 17236129
references: Neuron. 1995 Jun;14(6):1141-52
references: 7605629
references: Mol Cell Endocrinol. 2010 Feb 5;315(1-2):104-12
references: 19804812
references: Blood. 2011 Aug 4;118(5):1264-73
references: 21653327
references: Am J Med Genet A. 2011 Aug;155A(8):1884-96
references: 21744488
references: J Neurosci. 2012 Feb 29;32(9):2931-49
references: 22378868
references: Am J Med Genet A. 2008 Aug 1;146A(15):1994-8
references: 18627055
references: Genet Med. 2013 Jan;15(1):55-63
references: 22899094
references: J Neurobiol. 2003 Dec;57(3):337-49
references: 14608667
references: Hippocampus. 2006;16(10):875-90
references: 16941454
references: Eur J Hum Genet. 2012 Dec;20(12):1216-23
references: 22739344
references: Mol Syndromol. 2011 Sep;1(6):290-293
references: 22190898
references: J Proteomics. 2011 May 16;74(6):902-13
references: 21406263
references: Development. 2010 May;137(9):1553-62
references: 20356955
references: Blood. 2007 Dec 15;110(13):4206-13
references: 17827385