title: Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.
abstract: Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.
authors: Equipe 11, Institut National de la Santé et de la Recherche Médicale Unité 955, 94000 Créteil, France. veronique.pingault@inserm.fr
authors: Veronique
authors: V
authors: Pingault
authors: Virginie
authors: V
authors: Bodereau
authors: Viviane
authors: V
authors: Baral
authors: Severine
authors: S
authors: Marcos
authors: Yuli
authors: Y
authors: Watanabe
authors: Asma
authors: A
authors: Chaoui
authors: Corinne
authors: C
authors: Fouveaut
authors: Chrystel
authors: C
authors: Leroy
authors: Odile
authors: O
authors: Vérier-Mine
authors: Christine
authors: C
authors: Francannet
authors: Delphine
authors: D
authors: Dupin-Deguine
authors: Françoise
authors: F
authors: Archambeaud
authors: François-Joseph
authors: FJ
authors: Kurtz
authors: Jacques
authors: J
authors: Young
authors: Jérôme
authors: J
authors: Bertherat
authors: Sandrine
authors: S
authors: Marlin
authors: Michel
authors: M
authors: Goossens
authors: Jean-Pierre
authors: JP
authors: Hardelin
authors: Catherine
authors: C
authors: Dodé
authors: Nadege
authors: N
authors: Bondurand
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics* / Q000473:pathology; D005260:Female; D005602:France; D005697:Galactosides; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles; D017436:Kallmann Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000473:pathology*; D009833:Olfactory Pathways / Q000473:pathology*; D010957:Plasmids / Q000235:genetics; D055757:SOXE Transcription Factors / Q000235:genetics*
chemical_list: D005697:Galactosides; D007211:Indoles; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
references: Nat Genet. 2004 Apr;36(4):361-9
references: 15004559
references: Development. 2004 May;131(10):2349-58
references: 15102707
references: Am J Hum Genet. 2007 Dec;81(6):1169-85
references: 17999358
references: J Neurochem. 2010 Sep;114(6):1827-39
references: 20626560
references: Mol Biol Cell. 2008 Apr;19(4):1575-86
references: 18272785
references: Am J Med Genet A. 2008 Apr 15;146A(8):1038-41
references: 18348267
references: Hum Mol Genet. 2003 Apr 15;12(8):937-45
references: 12668617
references: J Biol Chem. 2006 Mar 3;281(9):5453-60
references: 16373334
references: PLoS Genet. 2012 Aug;8(8):e1002896
references: 22927827
references: Dev Biol. 2005 Jan 1;277(1):155-69
references: 15572147
references: Mech Dev. 2001 Dec;109(2):253-65
references: 11731238
references: Mol Brain. 2011 Sep 23;4:34
references: 21943152
references: Hum Genet. 2012 Mar;131(3):491-503
references: 21965087
references: Hum Mol Genet. 2001 Nov 15;10(24):2783-95
references: 11734543
references: Nat Genet. 1998 Jan;18(1):60-4
references: 9425902
references: Development. 2001 Nov;128(21):4113-25
references: 11684650
references: Pigment Cell Res. 2005 Apr;18(2):74-85
references: 15760336
references: Hum Mol Genet. 2000 Aug 12;9(13):1907-17
references: 10942418
references: Am J Med Genet A. 2005 Mar 15;133A(3):306-8
references: 15666308
references: Electrophoresis. 1997 Dec;18(15):2714-23
references: 9504803
references: Int J Biochem Cell Biol. 2010 Mar;42(3):411-6
references: 19808100
references: J Neuroendocrinol. 2010 Jul;22(7):743-53
references: 20646175
references: J Neurosci. 2011 May 4;31(18):6915-27
references: 21543621
references: J Clin Endocrinol Metab. 2002 Jun;87(6):2589-92
references: 12050219
references: AJNR Am J Neuroradiol. 2013 Jun-Jul;34(6):1257-63
references: 23237859
references: Clin Endocrinol (Oxf). 2001 Aug;55(2):163-74
references: 11531922
references: Biochem Biophys Res Commun. 2011 May 20;408(4):620-4
references: 21531202
references: J Clin Endocrinol Metab. 2003 May;88(5):2003-8
references: 12727945
references: Genes Dev. 2001 Jan 1;15(1):66-78
references: 11156606
references: Nat Genet. 2004 Jul;36(7):732-7
references: 15170213
references: Hum Mutat. 2011 Dec;32(12):1436-49
references: 21898658
references: Mol Cell Biol. 2000 May;20(9):3198-209
references: 10757804
references: J Clin Endocrinol Metab. 2012 May;97(5):E858-62
references: 22399515
references: Development. 2001 Oct;128(20):3949-61
references: 11641219
references: Hum Mutat. 2010 Apr;31(4):391-406
references: 20127975
references: Am J Med Genet A. 2009 Mar;149A(3):431-6
references: 19208381
references: Dev Biol. 2009 Nov 15;335(2):327-39
references: 19748502
references: Brain Res Mol Brain Res. 1989 Dec;6(4):311-26
references: 2687610
references: Development. 2003 Dec;130(25):6387-400
references: 14623827
references: Nucleic Acids Res. 2000 Aug 15;28(16):3047-55
references: 10931919
references: J Clin Endocrinol Metab. 2010 Jul;95(7):3491-6
references: 20463092
references: Oncogene. 2003 May 19;22(20):3024-34
references: 12789277
references: Neurosignals. 2012;20(3):147-58
references: 22456085
references: Eur J Hum Genet. 2009 Feb;17(2):139-46
references: 18985070
references: J Mol Med (Berl). 2010 May;88(5):507-14
references: 20130826
references: J Clin Invest. 2008 Aug;118(8):2822-31
references: 18596921
references: Dev Dyn. 2001 Sep;222(1):40-51
references: 11507768
references: Hum Mutat. 2012 Aug;33(8):1149-60
references: 22461308
references: Nat Genet. 2003 Apr;33(4):463-5
references: 12627230
references: J Clin Invest. 2010 Oct;120(10):3668-72
references: 20940512
references: Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21040-5
references: 21078992
references: Nat Genet. 1998 Feb;18(2):171-3
references: 9462749
references: Prog Neurobiol. 2010 Dec;92(4):517-32
references: 20837090
references: Development. 1994 Sep;120(9):2637-49
references: 7956838
references: Brain Res Mol Brain Res. 2000 Dec 8;84(1-2):141-5
references: 11113541
references: Hum Mutat. 2007 Jan;28(1):97-8
references: 17154279
references: Pediatr Dev Pathol. 1999 Nov-Dec;2(6):559-69
references: 10508880