Featured Research

from universities, journals, and other organizations

Sequencing a single genome yields cause of inherited bone disorder

Date:
June 21, 2010
Source:
Duke University Medical Center
Summary:
Combining new, whole-genome sequencing technology with classic genetic approaches to understanding inherited diseases, geneticists have discovered two gene mutations that cause metachondromatosis, a rare, heritable disorder that leads to bony growths, typically on hands and feet.

Combining new, whole-genome sequencing technology with classic genetic approaches to understanding inherited diseases, Duke University Medical Center geneticists and colleagues at Johns Hopkins have discovered two gene mutations that cause metachondromatosis, a rare, heritable disorder that leads to bony growths, typically on hands and feet.

They did it by sequencing the entire genome of just one individual. Results of the research are published in the journal PLoS Genetics.

Traditionally, rare inherited diseases (sometimes called "Mendelian" diseases, referring to those caused by mutations in a single gene and passed on through classic genetic patterns) have been studied using an approach called "linkage" in which a small number of markers are assessed for co-inheritance with the disease. The approach has been successful in many cases, but it can be very time-consuming and has been unsuccessful in as many as 1,500 studies where the presence of a gene inherited in Mendelian fashion is suspected, but has not been found, according to David Goldstein, PhD, director of the Center for Human Genome Variation at Duke.

Goldstein says a new strategy his team used to find mutations that cause metachondromatosis enables faster identification of Mendelian genes. "But perhaps more important, it may allow us to identify a lot of Mendelian genes that have been difficult to pin down with traditional analyses."

The opportunity to study genetic causes of metachondromatosis arose when Goldstein was lecturing at Johns Hopkins. Nara Sobreira, a graduate student in human genetics at Hopkins and a lead author of the study, mentioned to Goldstein that she was studying a small family that included six individuals across four generations affected with metachondromatosis.

The research team chose one member of the family and sequenced the entire genome of that person. Next, they used data from partial linkage data from other family members to identify areas in the genome where potentially causative mutations were most likely to be found. The analysis turned up six probable regions, implicating about one percent of the total genome. "This amount of genetic material would be very challenging to sequence using traditional strategies," said Goldstein.

The team used whole genome sequencing to zero in on a tiny string of 11 base pairs deleted from exon four of a gene called PTPN11. They found that all members of the family affected with metachondromatosis carried this mutation. The researchers confirmed PTPN11 alteration as the cause of the disease when they found a different mutation in the same gene in a second family with a history of the disease that also appeared in all of those affected with the disorder. Both mutations were predicted to lead to loss of function, or the inability of the body to make a protein necessary for normal development.

The researchers also sequenced exon 4 of PTPN11 -- the location of the causal mutations -- in 469 unrelated controls but did not find any mutations in the gene in that group.

Elizabeth Cirulli, a graduate student at Duke, a lead author and a member of Goldstein's team, says this is the first time that nonsense mutations in PTPN11 -- errors that disable a protein -- have been described in human disease. "The next step would be to figure out how this mutation directly contributes to the development of metachondromatosis," she said.

Sobreira said that finding the gene that causes metachondromatosis may also reveal the molecular basis of other diseases, like Maffucci syndrome and Ollier's disease, since individuals with those disorders share similar physical characteristics with those who have metachondromatosis.

Goldstein says the study adds to a small but growing list of examples where whole-genome sequencing approaches have successfully identified rare, high-penetrant risk factors for disease. Penetrance is a measure of how potent a mutation is in causing disease.

"The fact that linkage evidence was able to narrow our search for variants to just a fraction of what it might otherwise have been, cut our research time considerably," Goldstein says. He says that one interesting feature of this study is that the initial linkage evidence was only modest, approaching the sort of linkage evidence sometimes seen in large, multiple families for common diseases. "We are therefore hopeful that this sort of family-based sequencing might have utility in the study of genetic variants involved in more common diseases."

The study was supported by the Center for Human Genome Variation at Duke, the Kathryn and Alan Greenberg Center for Skeletal Dysplasias, the NIAID Center for HIV/AIDS Vaccine Immunology and the Bill & Melinda Gates Foundation.

Colleagues from Duke who contributed to the study include Dongliang Ge, Kevin Shianna, Jason Smith, Jessica Maia and Curtis Gumbs. Colleagues from Johns Hopkins include Dimitrios Avramopoulos, Elizabeth Wohler, Eric Stevens, Gretchen Oswald, Jonathan Pevsner, George Thomas, David Valle and Julie Hoover-Fong.


Story Source:

The above story is based on materials provided by Duke University Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Nara L. M. Sobreira, Elizabeth T. Cirulli, Dimitrios Avramopoulos, Elizabeth Wohler, Gretchen L. Oswald, Eric L. Stevens, Dongliang Ge, Kevin V. Shianna, Jason P. Smith, Jessica M. Maia, Curtis E. Gumbs, Jonathan Pevsner, George Thomas, David Valle, Julie E. Hoover-Fong, David B. Goldstein, Gregory S. Barsh. Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene. PLoS Genetics, 2010; 6 (6): e1000991 DOI: 10.1371/journal.pgen.1000991

Cite This Page:

Duke University Medical Center. "Sequencing a single genome yields cause of inherited bone disorder." ScienceDaily. ScienceDaily, 21 June 2010. <www.sciencedaily.com/releases/2010/06/100617185125.htm>.
Duke University Medical Center. (2010, June 21). Sequencing a single genome yields cause of inherited bone disorder. ScienceDaily. Retrieved July 24, 2014 from www.sciencedaily.com/releases/2010/06/100617185125.htm
Duke University Medical Center. "Sequencing a single genome yields cause of inherited bone disorder." ScienceDaily. www.sciencedaily.com/releases/2010/06/100617185125.htm (accessed July 24, 2014).

Share This




More Health & Medicine News

Thursday, July 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Idaho Boy Helps Brother With Disabilities Complete Triathlon

Idaho Boy Helps Brother With Disabilities Complete Triathlon

Newsy (July 23, 2014) An 8-year-old boy helped his younger brother, who has a rare genetic condition that's confined him to a wheelchair, finish a triathlon. Video provided by Newsy
Powered by NewsLook.com
Thousands Who Can't Afford Medical Care Flock to Free US Clinic

Thousands Who Can't Afford Medical Care Flock to Free US Clinic

AFP (July 23, 2014) America may be the world’s richest country, but in terms of healthcare, the World Health Organisation ranks it 37th. Thousands turned out for a free clinic run by "Remote Area Medical" with a visit from the Governor of Virginia. Duration: 2:40 Video provided by AFP
Powered by NewsLook.com
Stone Fruit Listeria Scare Causes Sweeping Recall

Stone Fruit Listeria Scare Causes Sweeping Recall

Newsy (July 22, 2014) The Wawona Packing Company has issued a voluntary recall on the stone fruit it distributes due to a possible Listeria outbreak. Video provided by Newsy
Powered by NewsLook.com
Huge Schizophrenia Study Finds Dozens Of New Genetic Causes

Huge Schizophrenia Study Finds Dozens Of New Genetic Causes

Newsy (July 22, 2014) The 83 new genetic markers could open dozens of new avenues for schizophrenia treatment research. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins