Discovery Leads to Better Understanding of Polydactyly

The discovery helps illuminate the shaping of limb structures in the womb.

These images compare normal hands to abnormal ones caused by the congenital disorder polydactyly. The first four images, from left, compare a normal hand with ones that, with differing severity, have an extra finger near the thumb. The fifth image is of a normal hand and is juxtaposed by a limb that exhibits a defect in which the extra finger is fused to the normal finger.
Image credit: Collected by Laura Quintana Rio

“This condition—polydactyly—can be present as a single abnormality in the newborn,” says Dr. Licia Selleri, an associate professor in the Department of Cell and Developmental Biology and in the Feil Family Brain and Mind Research Institute. “Unfortunately, many times, it is associated with other, very serious organ abnormalities, so it comes as a syndrome.”

Polydactyly occurs in about 1 out of 500 births worldwide. The disorder may consist of one superfluous finger or toe, or it can manifest as multiple extra digits.

To pinpoint the gene involved in these aberrations, researchers at Weill Cornell injected male mice with a chemical widely used to induce DNA mutations, N-ethyl-N-nitrosourea, or ENU. Repeated cross-breeding of the mutant mice led to striking abnormalities in their offspring, generating a mouse model with multiple digits and craniofacial defects.

“We cloned the gene, and this takes a lot of work,” Dr. Selleri says. “You have to sift through the whole genome to try to find which gene has been mutated by this chemical.”

The mutation in the gene Vps25 was induced by exposure of mice to the chemical N-ethyl-N-nitrosourea, or ENU. Dr. Selleri’s lab discovered that the defect causes an intra-cellular machine known as ESCRT to behave abnormally.
Image credit: Karen Handschuh, Jennifer Feenstra and Matthew Koss.

What researchers isolated is a mutant line that carries the disruption of the gene encoding vacuolar protein sorting 25, or Vps25. The protein is a subunit of ESCRT-II (Endosomal Sorting Complex Required for Transport protein II). The complex enables a unique mode of membrane remodeling, which allows damaged proteins to be recycled or destroyed. The analysis of the 3-D structure of the mutated Vps25/ESCRT protein was conducted by postdoctoral fellow Dr. Michelle A. Sahai, and by Dr. Harel Weinstein, chairman of Weill Cornell’s Department of Physiology and Biophysics.

“This discovery is important as it reveals unexpected mechanisms underlying the establishment of digit number,” Dr. Selleri says of the findings, published in Cell Reports. Three postdoctoral researchers formerly in Dr. Selleri’s lab — Drs. Karen Handschuh, Jennifer Feenstra and Matthew Koss — co-led the study. It only characterized digit abnormalities in the developing mouse embryo, but Dr. Selleri hopes to evaluate craniofacial defects in subsequent research.

Affected digits are typically stunted and abnormally shaped, and they often veer in an abnormal direction. Pre-axial polydactyly is the development of an extraneous finger on the thumb side of the hand. In a specific defect known as synpolydactyly, an additional digit is fused to a normal digit.

Such birth defects are under-reported and are likely to occur more commonly than records suggest. They often require surgical repair followed by physical therapy and possible future operations as a child grows.

“Since this congenital defect appears both in isolation and in conjunction with other abnormalities, gaining fundamental knowledge of these genetic pathways is vital to developing effective genetic diagnostic screens and directed therapies,” Dr. Selleri says.

Drs. Elizabeth Lacy and Kathryn Anderson, both of the Sloan Kettering Institute’s developmental biology program, also contributed to the study.

Weill Cornell Medical College