title: SAMS, a syndrome of short stature, auditory-canal atresia, mandibular hypoplasia, and skeletal abnormalities is a unique neurocristopathy caused by mutations in Goosecoid.
abstract: Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) has been reported previously to be a rare, autosomal-recessive developmental disorder with other, unique rhizomelic skeletal anomalies. These include bilateral humeral hypoplasia, humeroscapular synostosis, pelvic abnormalities, and proximal defects of the femora. To identify the genetic basis of SAMS, we used molecular karyotyping and whole-exome sequencing (WES) to study small, unrelated families. Filtering of variants from the WES data included segregation analysis followed by comparison of in-house exomes. We identified a homozygous 306 kb microdeletion and homozygous predicted null mutations of GSC, encoding Goosecoid homeobox protein, a paired-like homeodomain transcription factor. This confirms that SAMS is a human malformation syndrome resulting from GSC mutations. Previously, Goosecoid has been shown to be a determinant at the Xenopus gastrula organizer region and a segment-polarity determinant in Drosophila. In the present report, we present data on Goosecoid protein localization in staged mouse embryos. These data and the SAMS clinical phenotype both suggest that Goosecoid is a downstream effector of the regulatory networks that define neural-crest cell-fate specification and subsequent mesoderm cell lineages in mammals, particularly during shoulder and hip formation. Our findings confirm that Goosecoid has an essential role in human craniofacial and joint development and suggest that Goosecoid is an essential regulator of mesodermal patterning in mammals and that it has specific functions in neural crest cell derivatives.
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.forename: Alexander P A
authors.initials: AP
authors.lastname: Stegmann
authors.forename: Zakia A
authors.initials: ZA
authors.lastname: Abdelhamed
authors.forename: Alistair
authors.initials: A
authors.lastname: Calder
authors.forename: Shabana
authors.initials: S
authors.lastname: Khan
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.forename: Virginia
authors.initials: V
authors.lastname: Clowes
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.forename: Neeti
authors.initials: N
authors.lastname: Ghali
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.forename: Angus
authors.initials: A
authors.lastname: Dobbie
authors.forename: Constance T R M
authors.initials: CT
authors.lastname: Stumpel
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D002648:Child; D004252:DNA Mutational Analysis; D004392:Dwarfism / Q000235:genetics*; D004424:Ear Canal / Q000002:abnormalities*; D005260:Female; D056726:Genetic Association Studies; D051956:Goosecoid Protein / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008334:Mandible / Q000002:abnormalities*; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D055815:Young Adult
chemical_list: D051956:Goosecoid Protein