Journal article
Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly
American journal of medical genetics. Part A, Vol.143(1), pp.27-32
2007
DOI: 10.1002/ajmg.a.31563
PMID: 17152067
Abstract
Spatio-temporal expression of sonic hedgehog (SHH) is driven by a regulatory element (ZRS) that lies 1 Mb upstream from SHH. Point mutations within the highly conserved ZRS have been described in the hemimelic extra toes mouse and in four families with preaxial polydactyly [Lettice et al., 2003]. Four North American Caucasian families were identified with autosomal dominant triphalangeal thumb. DNA from 20 affected and 36 unaffected family members was evaluated by sequence analysis of a 774-bp highly conserved ZRS contained within LMBR1 intron 5. Mutations within ZRS were identified in three of four families. In pedigree A and C, a novel A/G transition was identified near the 5' end of ZRS at bp 739 that segregated with disease or carrier status. Pedigree A, described previously [Dobbs et al., 2000], is a large family with 19 affected members who exhibit a milder phenotype, including predominantly triphalangeal thumbs and low penetrance (82%) relative to other families. Pedigree C is a small family with two affected family members with triphalangeal thumb, and one affected with both triphalangeal thumb and preaxial polydactyly. A novel C/G mutation at bp 621 was identified in pedigree B that segregated with the disease in all four affected individuals who manifested both preaxial polydactyly and triphalangeal thumb. Both mutations alter putative Cdx transcription factor binding sites. Mutations within ZRS appear to be a common cause of familial triphalangeal thumb and preaxial polydactyly. A genotype/phenotype correlate is suggested by pedigree A, whose mutation lies near the 5' end of ZRS; this family demonstrates a higher rate of nonpenetrance and milder phenotype. However, modifier genes may be contributing to the milder phenotype in this family.
Details
- Title: Subtitle
- Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly
- Creators
- Christina A GURNETT - Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United StatesAnne M BOWCOCK - Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United StatesFrederick R DIETZ - Department of Orthopedic Surgery and Rehabilitation, University of Iowa College of Medicine, Iowa City, Iowa, United StatesJose A MORCUENDE - Department of Orthopedic Surgery and Rehabilitation, University of Iowa College of Medicine, Iowa City, Iowa, United StatesJeffrey C MURRAY - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa, United StatesMatthew B DOBBS - Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
- Resource Type
- Journal article
- Publication Details
- American journal of medical genetics. Part A, Vol.143(1), pp.27-32
- DOI
- 10.1002/ajmg.a.31563
- PMID
- 17152067
- NLM abbreviation
- Am J Med Genet A
- ISSN
- 1552-4825
- eISSN
- 1552-4833
- Publisher
- Wiley-Liss; Hoboken, NJ
- Language
- English
- Date published
- 2007
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Orthopedics and Rehabilitation; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984025310502771
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