title: AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome).
abstract: MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.
authors.affiliation: 1] Inserm, U910, Faculté de Médecine de La Timone, Marseille, France [2] Aix Marseille Université, Faculté de Médecine, Marseille, France [3] Assistance Publique Hôpitaux de Marseille, Département de Génétique Médicale et de Biologie Cellulaire, Hôpital d'Enfants de La Timone, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cacciagli
authors.affiliation: 1] Inserm, U910, Faculté de Médecine de La Timone, Marseille, France [2] Aix Marseille Université, Faculté de Médecine, Marseille, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Desvignes
authors.affiliation: Assistance Publique Hôpitaux de Marseille, Service de Neuroradiologie, Hôpital de La Timone, Marseille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Girard
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Delepine
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.affiliation: 1] Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France [2] Fondation Jean Dausset - CEPH, Paris, France.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: 1] Inserm, U910, Faculté de Médecine de La Timone, Marseille, France [2] Aix Marseille Université, Faculté de Médecine, Marseille, France [3] Assistance Publique Hôpitaux de Marseille, Département de Génétique Médicale et de Biologie Cellulaire, Hôpital d'Enfants de La Timone, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.affiliation: Geisinger Health System, Danville, PA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.affiliation: Departments of Pediatrics and Neurology, University of Washington, Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: 1] Inserm, U910, Faculté de Médecine de La Timone, Marseille, France [2] Aix Marseille Université, Faculté de Médecine, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
mesh_terms: D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001480:Basal Ganglia Diseases / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D003616:Dandy-Walker Syndrome / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012640:Seizures / Q000175:diagnosis / Q000235:genetics*
chemical_list: C516800:AP1S2 protein, human; D034002:Adaptor Protein Complex sigma Subunits