Gene dosage of the transcription factor Fingerin (bHLHA9) affects digit development and links syndactyly to ectrodactyly.
Distal limb deformities are congenital malformations with phenotypic variability, genetic heterogeneity and complex inheritance. Among these, split-hand/foot malformation is an ectrodactyly with missing central fingers, yielding a lobster claw-like hand, which when combined with long-bone deficiency is defined as split-hand/foot malformation and long-bone deficiency (SHFLD) that is genetically heterogeneous. Copy number variation (CNV) consisting of 17p13.3 duplication was identified in unrelated pedigrees, underlying SHFLD3 (OMIM 612576). Although the transcription factor Fingerin (bHLHA9) is the only complete gene in the critical region, its biological role is not yet known and there are no data supporting its involvement in mammalian limb development. We have generated knockout mice in which only the entire coding region of Fingerin was deleted, and indeed found that most null mice display some limb defects. These include various levels of simple asymmetrical syndactyly, characterized by webbed fingers, generated by incomplete separation of soft, but not skeletal, tissues between forelimb digits 2 and 3. As expected, hand pads of Fingerin null embryos exhibited reduced apoptosis between digital rays 2 and 3. This defect was shown to cause syndactyly when the same limbs were grown ex vivo following the apoptosis assay. Extrapolating from mouse data, we suggest that Fingerin loss-of-function in humans may underlie MSSD syndactyly (OMIM 609432), which was mapped to the same locus. Taken together, Fingerin gene dosage links two different congenital limb malformations, syndactyly and ectrodactyly, which were previously postulated to share a common etiology. These results add limb disorders to the growing list of diseases resulting from CNV.
Department of Cell and Developmental Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Omri
O
Schatz
Department of Cell and Developmental Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Erez
E
Langer
Department of Cell and Developmental Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel nissim.ben-arie@mail.huji.ac.il.
Nissim
N
Ben-Arie
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D005385:Fingers / Q000002:abnormalities*; D005552:Forelimb / Q000002:abnormalities; D018628:Gene Dosage; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012737:Sex Factors; D013576:Syndactyly / Q000235:genetics* / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; C000598252:bHLHA9 protein, mouse