Analysis of DNA elements that modulate myosin VIIA expression in humans.

Abstract

Usher syndromeIb (USH1B), an autosomal recessive disorder caused by mutations in myosin VIIa (MYO7A), is characterized by congenital profound hearing loss, vestibular abnormalities and retinitis pigmentosa. Promoter elements in the 5 kb upstream of the translation start were identified using adult retinal pigment epithelium cells (ARPE-19) as a model system. A 160 bp minimal promoter within the first intron was active in ARPE-19 cells, but not in HeLa cells that do not express MYO7A. A 100 bp sequence, 5' of the first exon, and repeated with 90% homology within the first intron, appeared to modulate expression in both cell lines. Segments containing these elements were screened by heteroduplex analysis. No heteroduplexes were detected in the minimal promoter, suggesting that this sequence is conserved. A -2568 A>T transversion in the 5' 100 bp repeat, eliminating a CCAAT element, was found only in USH1B patients. However, in all 5 families, -2568 A>T was in cis with the same missense mutation in the myosin VIIa tail (Arg1240Gln), and 4 of the 5 families were Dutch. These observations suggest either 1) linkage disequilibrium or 2)that a combination of a promoter mutation with a less active myosin VIIa protein results in USH1B.

• Authors: D J Orten, M D Weston, P M Kelley, C W Cremers, M Wagenaar, S G Jacobson, W J Kimberling
• Journal: Human mutation (Hum Mutat) Vol. 14 Issue 4 Pg. 354 (Oct 1999) ISSN: 1098-1004 [Electronic] United States
• PMID: 10502787 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 1999 Wiley-Liss, Inc.

Chemical References

• MYO7A protein, human
• Myosin VIIa
• Myosins
• Dyneins

Topics

• Cells, Cultured
• Chromosomes, Human, Pair 11
• DNA Mutational Analysis
• Dyneins
• Gene Expression Regulation
• HeLa Cells
• Hearing Loss, Sensorineural (genetics, metabolism)
• Humans
• Mutation, Missense
• Myosin VIIa
• Myosins (biosynthesis, genetics)
• Pigment Epithelium of Eye (metabolism)
• Promoter Regions, Genetic
• Retinitis Pigmentosa (genetics, metabolism)
• Syndrome
• Vestibular Diseases (genetics, metabolism)