title: BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome.
abstract: BMP4 loss-of-function mutations and deletions have been shown to be associated with ocular, digital, and brain anomalies, but due to the paucity of these reports, the full phenotypic spectrum of human BMP4 mutations is not clear. We screened 133 patients with a variety of ocular disorders for BMP4 coding region mutations or genomic deletions. BMP4 deletions were detected in two patients: a patient affected with SHORT syndrome and a patient with anterior segment anomalies along with craniofacial dysmorphism and cognitive impairment. In addition to this, three intragenic BMP4 mutations were identified. A patient with anophthalmia, microphthalmia with sclerocornea, right-sided diaphragmatic hernia, and hydrocephalus was found to have a c.592C >T (p.R198X) nonsense mutation in BMP4. A frameshift mutation, c.171dupC (p.E58RfsX17), was identified in two half-siblings with anophthalmia/microphthalmia, discordant developmental delay/postaxial polydactyly, and poor growth as well as their unaffected mother; one affected sibling carried an additional BMP4 mutation in the second allele, c.362A > G (p.H121R). This is the first report indicating a role for BMP4 in SHORT syndrome, Axenfeld-Rieger malformation, growth delay, macrocephaly, and diaphragmatic hernia. These results significantly expand the number of reported loss-of-function mutations, further support the critical role of BMP4 in ocular development, and provide additional evidence of variable expression/non-penetrance of BMP4 mutations.
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Reis
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Tyler
authors.forename: Kala F
authors.initials: KF
authors.lastname: Schilter
authors.forename: Omar
authors.initials: O
authors.lastname: Abdul-Rahman
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Innis
authors.forename: Beth A
authors.initials: BA
authors.lastname: Kozel
authors.forename: Adele S
authors.initials: AS
authors.lastname: Schneider
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Bardakjian
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lose
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Elena V
authors.initials: EV
authors.lastname: Semina
mesh_terms: D000595:Amino Acid Sequence; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D005123:Eye / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics*; D007223:Infant; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009397:Nephrocalcinosis / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4