Contact: Cathy Yarbrough
Called McKusick-Kaufman syndrome, or MKS, the condition is the first human disorder to be attributed to a mutation in a gene affecting a type of molecule called a chaperonin, the researchers report in the May issue of the journal Nature Genetics. Chaperonins are sometimes called "protein cages": they protect cells by capturing and refolding misshapen proteins that could otherwise interfere with normal cellular functions.
Females with MKS are affected by hydrometrocolpos (accumulation of fluids in the uterus and vagina). Both males and females have a form of polydactyly (the presence of extra fingers or toes) and congenital heart disease.
The disorder is most serious in female infants in whom the hydrometrocolpos can cause death because of lung compression complications.
MKS is inherited in a recessive pattern, meaning that a child must inherit two altered genes, one from each parent, to be affected. Between one and three percent of the Amish people of Lancaster County Pennsylvania are believed to be unaffected carriers of the disease, having just one copy of the altered gene.
In their study, the researchers looked at a region of chromosome 20 that they knew contained the gene responsible for the syndrome, based on earlier genetic analysis of the Old Order Amish population. A technique called sample sequencing was then used to find candidate genes in that region. One of those genes, dubbed MKKS, was altered in a sample from an Amish patient as well as in a sample from a non-Amish patient diagnosed with MKKS. In both people, "misspellings" in the genetic code were found that would disrupt the function of the MKKS gene.
The researchers noted that the amino acids coded by the MKKS gene appeared very similar to those that make up the chaperonin family of proteins. Remarkably, the most similar gene to MKKS is a gene found in an ancient heat-loving bacterium, Thermus acidophilus. Although the function of the protein made by the MKKS gene is unclear, the researchers say that it may be involved in the processing of other proteins in the development of limbs, the heart and reproductive system.
"The MKKS gene mutations suggest that protein integrity may be critical to developmental processes," said Dr. Leslie Biesecker, senior author of the study and head of the human development section in the NHGRI's genetic disease research branch.
"By studying these rare or so-called orphan diseases, we learn more about both normal and abnormal human development," he added. "We are grateful to the Amish families who assisted us to find this gene. It is hoped that we can develop a screening process for carrier couples so that their pregnancies can be monitored for hydrometrocolpos by ultrasound. Affected girls could be delivered in a setting that would allow rapid surgical correction that could be life saving."