title: The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly.
abstract: Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.
authors.affiliation: Departments of Pediatrics and Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4399, USA.
authors.forename: L
authors.initials: L
authors.lastname: Nanni
authors.forename: J E
authors.initials: JE
authors.lastname: Ming
authors.forename: M
authors.initials: M
authors.lastname: Bocian
authors.forename: K
authors.initials: K
authors.lastname: Steinhaus
authors.forename: D W
authors.initials: DW
authors.lastname: Bianchi
authors.forename: C
authors.initials: C
authors.lastname: Die-Smulders
authors.forename: A
authors.initials: A
authors.lastname: Giannotti
authors.forename: K
authors.initials: K
authors.lastname: Imaizumi
authors.forename: K L
authors.initials: KL
authors.lastname: Jones
authors.forename: M D
authors.initials: MD
authors.lastname: Campo
authors.forename: R A
authors.initials: RA
authors.lastname: Martin
authors.forename: P
authors.initials: P
authors.lastname: Meinecke
authors.forename: M E
authors.initials: ME
authors.lastname: Pierpont
authors.forename: N H
authors.initials: NH
authors.lastname: Robin
authors.forename: I D
authors.initials: ID
authors.lastname: Young
authors.forename: E
authors.initials: E
authors.lastname: Roessler
authors.forename: M
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000595:Amino Acid Sequence; D004247:DNA / Q000032:analysis*; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D015534:Trans-Activators
chemical_list: D053823:Hedgehog Proteins; D011506:Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D004247:DNA