Medical genetics

Hand and bone patterning gene

The discovery of a rare genetic mutation sheds new light on bone and limb development

Published online 22 June 2011

Hand X-ray showing the developmental abnormalities caused by TPBS

© 2011 American Society of Human Genetics

Brachydactyly is a genetic disorder characterized by disproportionately short fingers and toes. There are many forms of brachydactyly, and children with recessive Temtamy preaxial brachydactyly syndrome (TPBS) are known to develop fingers that look like thumbs (see image). Bruno Reversade at the A*STAR Institute of Medical Biology and co-workers1 have now discovered the genetic mutation that causes this rare form of brachydactyly.

The researchers took DNA samples from a Jordanian family comprising five members, two of which were affected by TPBS. They compared the genetic makeup of affected individuals with that of unaffected individuals and identified 177 candidate genes that might have caused the genetic disorder.   

The researchers sequenced all these candidate genes using a high-throughput DNA sequencing technology and discovered the specific mutation that is responsible for TPBS. The mutation lies in the gene CHSY1, which encodes the enzyme CHSY1 of the chondroitin synthase family.

The mutation results in the expression of a truncated form of CHSY1, which lacks catalytic activity. As chondroitin sulfate is an important structural component of cartilage and bone, CHSY1 might play a critical role in its biosynthesis.

The researchers confirmed their hypothesis by showing that an absence of the functional CHSY1 enzyme caused massive production of the protein JAG1 and activation of the signaling protein NOTCH to which it binds. They found that experimentally depleting CHSY1 using RNA inhibition led to enhanced activity of fetal bone-forming cells in vitro. Similar depletion of CHSY1 in cultured cancer cells led to greatly increased expression of JAG2, another NOTCH-binding protein.

They found that experimentally blocking CHSY1 expression in zebrafish embryos led to the development of morphological abnormalities, partly mirroring those found in brachydactyly patients. These defects included impaired skeletal, pectoral fin and retinal development, and were associated with increased NOTCH output.

“It may seem counter-intuitive to study digit formation in fish, as they have none,” says Reversade. “However, pectoral fins are analogous to the human hands and so we hypothesized that CHSY1’s role may be conserved in fish during limb development, and indeed it was.”

These findings increase our understanding of hand development by revealing another layer of genetic regulation in an already fine-tuned system. “But this is to be expected,” says Reversade. “One just needs to look at whales and bats, for instance. Both are mammals like humans, but each have very different hand morphology to swim or fly, respectively.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology


  1. Tian, J. et al. Loss of CHSY1, a secreted FRINGE enzyme, causes syndromic brachydactyly in humans via increased NOTCH signaling. American Journal of Human Genetics 87, 768–778 (2010). | article