A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb.
A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T&a...
| मुख्य लेखकों: | , , , , , , |
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| स्वरूप: | Journal article |
| भाषा: | English |
| प्रकाशित: |
Oxford University Press
2008
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| _version_ | 1826276499778437120 |
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| author | Furniss, D Lettice, L Taylor, I Critchley, P Giele, H Hill, R Wilkie, A |
| author_facet | Furniss, D Lettice, L Taylor, I Critchley, P Giele, H Hill, R Wilkie, A |
| author_sort | Furniss, D |
| collection | OXFORD |
| description | A locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T>C variant in the human ZRS, previously thought to represent a neutral polymorphism, acts as a dominant allele with reduced penetrance. We found this variant in three independently ascertained probands from southern England with triphalangeal thumb, demonstrated significant linkage of the phenotype to the variant (LOD = 4.1), and identified a shared microsatellite haplotype around the ZRS, suggesting that the probands share a common ancestor. An individual homozygous for the 295C allele presented with isolated bilateral triphalangeal thumb resembling the heterozygous phenotype, suggesting that the variant is largely dominant to the wild-type allele. As a functional test of the pathogenicity of the 295C allele, we utilized a mutated ZRS construct to demonstrate that it can drive ectopic anterior expression of a reporter gene in the developing mouse forelimb. We conclude that the 295T>C variant is in fact pathogenic and, in southern England, appears to be the most common cause of triphalangeal thumb. Depending on the dispersal of the founding mutation, it may play a wider role in the aetiology of this disorder. |
| first_indexed | 2024-03-06T23:14:53Z |
| format | Journal article |
| id | oxford-uuid:66ca6085-8849-4a71-b031-c8912fcbe87d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:14:53Z |
| publishDate | 2008 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:66ca6085-8849-4a71-b031-c8912fcbe87d2022-03-26T18:34:11ZA variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:66ca6085-8849-4a71-b031-c8912fcbe87dEnglishSymplectic Elements at OxfordOxford University Press2008Furniss, DLettice, LTaylor, ICritchley, PGiele, HHill, RWilkie, AA locus for triphalangeal thumb, variably associated with pre-axial polydactyly, was previously identified in the zone of polarizing activity regulatory sequence (ZRS), a long range limb-specific enhancer of the Sonic Hedgehog (SHH) gene at human chromosome 7q36.3. Here, we demonstrate that a 295T>C variant in the human ZRS, previously thought to represent a neutral polymorphism, acts as a dominant allele with reduced penetrance. We found this variant in three independently ascertained probands from southern England with triphalangeal thumb, demonstrated significant linkage of the phenotype to the variant (LOD = 4.1), and identified a shared microsatellite haplotype around the ZRS, suggesting that the probands share a common ancestor. An individual homozygous for the 295C allele presented with isolated bilateral triphalangeal thumb resembling the heterozygous phenotype, suggesting that the variant is largely dominant to the wild-type allele. As a functional test of the pathogenicity of the 295C allele, we utilized a mutated ZRS construct to demonstrate that it can drive ectopic anterior expression of a reporter gene in the developing mouse forelimb. We conclude that the 295T>C variant is in fact pathogenic and, in southern England, appears to be the most common cause of triphalangeal thumb. Depending on the dispersal of the founding mutation, it may play a wider role in the aetiology of this disorder. |
| spellingShingle | Furniss, D Lettice, L Taylor, I Critchley, P Giele, H Hill, R Wilkie, A A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. |
| title | A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. |
| title_full | A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. |
| title_fullStr | A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. |
| title_full_unstemmed | A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. |
| title_short | A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. |
| title_sort | variant in the sonic hedgehog regulatory sequence zrs is associated with triphalangeal thumb and deregulates expression in the developing limb |
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