title: Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain.
abstract: Waardenburg syndrome type 4 (WS4), also called Shah-Waardenburg syndrome, is a rare neurocristopathy that results from the absence of melanocytes and intrinsic ganglion cells of the terminal hindgut. WS4 is inherited as an autosomal recessive trait attributable to EDN3 or EDNRB mutations. It is inherited as an autosomal dominant condition when SOX10 mutations are involved. We report on three unrelated WS4 patients with growth retardation and an as-yet-unreported neurological phenotype with impairment of both the central and autonomous nervous systems and occasionally neonatal hypotonia and arthrogryposis. Each of the three patients was heterozygous for a SOX10 truncating mutation (Y313X in two patients and S251X [corrected] in one patient). The extended spectrum of the WS4 phenotype is relevant to the brain expression of SOX10 during human embryonic and fetal development. Indeed, the expression of SOX10 in human embryo was not restricted to neural-crest-derived cells but also involved fetal brain cells, most likely of glial origin. These data emphasize the important role of SOX10 in early development of both neural-crest-derived tissues, namely melanocytes, autonomic and enteric nervous systems, and glial cells of the central nervous system.
authors.affiliation: Département de Génétique et Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Hôpital Necker-Enfants Malades, 75743 Paris, France.
authors.forename: R L
authors.initials: RL
authors.lastname: Touraine
authors.forename: T
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: E
authors.initials: E
authors.lastname: Manceau
authors.forename: E
authors.initials: E
authors.lastname: Korsch
authors.forename: P
authors.initials: P
authors.lastname: Sarda
authors.forename: V
authors.initials: V
authors.lastname: Pingault
authors.forename: F
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: A
authors.initials: A
authors.lastname: Pelet
authors.forename: J
authors.initials: J
authors.lastname: Augé
authors.forename: A
authors.initials: A
authors.lastname: Nivelon-Chevallier
authors.forename: A M
authors.initials: AM
authors.lastname: Holschneider
authors.forename: M
authors.initials: M
authors.lastname: Munnes
authors.forename: W
authors.initials: W
authors.lastname: Doerfler
authors.forename: M
authors.initials: M
authors.lastname: Goossens
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: M
authors.initials: M
authors.lastname: Vekemans
authors.forename: S
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D001341:Autonomic Nervous System / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D002648:Child; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006579:Heterozygote; D006609:High Mobility Group Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D007231:Infant, Newborn; D008297:Male; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D055757:SOXE Transcription Factors; D017384:Sequence Deletion / Q000235:genetics*; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics* / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D012333:RNA, Messenger; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D014157:Transcription Factors