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BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome. Hum Genet 2011 Oct;130(4):495-504

Date

02/23/2011

Pubmed ID

21340693

Pubmed Central ID

PMC3178759

DOI

10.1007/s00439-011-0968-y

Scopus ID

2-s2.0-80054867601 (requires institutional sign-in at Scopus site)   93 Citations

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.

Author List

Reis LM, Tyler RC, Schilter KF, Abdul-Rahman O, Innis JW, Kozel BA, Schneider AS, Bardakjian TM, Lose EJ, Martin DM, Broeckel U, Semina EV

Authors

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin
Kala Schilter in the CTSI department at Medical College of Wisconsin - CTSI
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Bone Morphogenetic Protein 4
Child
Child, Preschool
Chromosome Aberrations
Eye
Female
Growth Disorders
Humans
Hypercalcemia
Infant
Male
Metabolic Diseases
Molecular Sequence Data
Mutation
Nephrocalcinosis
Pedigree
Sequence Homology, Amino Acid