Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS

TY - JOUR

T1 - Preaxial polydactyly/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long-range cis-regulatory element ZRS

AU - Farooq, Muhammad

AU - Troelsen, Jesper T

AU - Boyd, Mette

AU - Eiberg, Hans

AU - Hansen, Lars

AU - Hussain, Muhammad Sajid

AU - Rehman, Shoaib ur

AU - Azhar, Aysha

AU - Ali, Amjad

AU - Bakhtiar, Syeda Marriam

AU - Tommerup, Niels

AU - Baig, Shahid Mahmood

AU - Kjaer, Klaus W

PY - 2010/6

Y1 - 2010/6

N2 - A cis-regulatory sequence also known as zone of polarizing activity (ZPA) regulatory sequence (ZRS) located in intron 5 of LMBR1 is essential for expression of sonic hedgehog (SHH) in the developing posterior limb bud mesenchyme. Even though many point mutations causing preaxial duplication defects have been reported in ZRS, the underlying regulatory mechanism is still unknown. In this study, we analyzed the effect on transcription factor binding of a novel ZRS point mutation (463T>G) in a Pakistani family with preaxial polydactyly and triphalangeal thumb. Electrophoretical mobility shift assay demonstrated a marked difference between wild-type and the mutant probe, which uniquely bound one or several transcription factors extracted from Caco-2 cells. This finding supports a model in which ectopic anterior SHH expression in the developing limb results from abnormal binding of one or more transcription factors to the mutant sequence.

AB - A cis-regulatory sequence also known as zone of polarizing activity (ZPA) regulatory sequence (ZRS) located in intron 5 of LMBR1 is essential for expression of sonic hedgehog (SHH) in the developing posterior limb bud mesenchyme. Even though many point mutations causing preaxial duplication defects have been reported in ZRS, the underlying regulatory mechanism is still unknown. In this study, we analyzed the effect on transcription factor binding of a novel ZRS point mutation (463T>G) in a Pakistani family with preaxial polydactyly and triphalangeal thumb. Electrophoretical mobility shift assay demonstrated a marked difference between wild-type and the mutant probe, which uniquely bound one or several transcription factors extracted from Caco-2 cells. This finding supports a model in which ectopic anterior SHH expression in the developing limb results from abnormal binding of one or more transcription factors to the mutant sequence.

U2 - 10.1038/ejhg.2009.225

DO - 10.1038/ejhg.2009.225

M3 - Journal article

C2 - 20068592

SN - 1018-4813

VL - 18

SP - 733

EP - 736

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 6

ER -