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Thomas Ralph William Nixon, Allan Richards, Laura Towns, Richard Sandford, Martin Snead; BMP4 loss of function mutation is a cause of autosomal dominant Stickler syndrome with associated renal dysplasia in one family. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6041.
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Stickler syndrome is an inherited disorder that can lead to joint problems, hearing difficulties and retinal detachment. Several genes coding for collagen types II, IX and XI are known to be involved but some families are yet to have a mutation identified. We investigate the role of mutation in the gene for the growth factor BMP4 in a family with clinical Stickler syndrome with associated renal dysplasia.
Next generation sequencing was performed of the coding region for COL2A1, COL11A1 and a panel of genes known to cause congenital anomalies of the kidney and urinary tract. Pedigree mapping was performed and each available family member examined for ophthalmic, audiological or dysmorphic features. Four affected and one unaffected family members had fluorescent sequencing analysis to assess for presence of the familial variant. Skin fibroblasts were cultured with and without emetine, the mRNA extracted and analysed by Sanger sequencing to assess whether the mutation within BMP4 was causing nonsense-mediated decay.
A novel heterozygous BMP4 premature stop mutation was identified, c. 130G>T, p.(Gly44Ter), which segregated in the family with clinical features of Stickler syndrome. Nonsense-mediated decay was not observed. No mutation was detected in COL2A1 or COL11A1. Clinical features identified included myopia, abnormal vitreous, retinal detachment, hearing loss, arthritis and, in one individual, renal dysplasia.
This is the first example of a mutation in this gene causing Stickler syndrome. The phenotype is comparable to autosomal dominant type 2 Stickler syndrome caused by a COL11A1 mutation, with no clinically distinguishing features. BMP4 is a growth factor known to contribute to eye development in animal models and mutations in humans have been linked to microphthalmia and anophthalmia. The mutation identified within this family further demonstrates the importance of BMP4 in eye development. We suggest BMP4 should be added to standard gene panels for Stickler syndrome.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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