Study uncovers mutation responsible for Noonan Syndrome

Dec 04, 2006

Scientists have discovered that mutations in a gene known as SOS1 account for many cases of Noonan syndrome (NS), a common childhood genetic disorder which occurs in one in 1,000-2,500 live births. NS is characterized by short stature, facial abnormalities, and learning disabilities, as well as heart problems and predisposition to leukemia.

Led by researchers at Harvard Medical School-Partners Healthcare Center for Genetics and Genomics (HPCGG) and Beth Israel Deaconess Medical Center (BIDMC), the findings are reported in the December issue of Nature Genetics, which appears on-line today.

"Noonan syndrome is the most common single gene cause of congenital heart disease," explains co-senior author Benjamin Neel, MD, PhD, Director of the Division of Cancer Biology at BIDMC and professor of medicine at Harvard Medical School (HMS).

"Although previous work had identified mutations in the PTPN11 gene as the cause of Noonan syndrome in nearly 50 percent of cases [and mutations in an oncogene known as KRAS in a small subset of severe cases] the identity of the gene or genes responsible for fully half the cases had not been elucidated," Neel said.

To identify candidate genes, a group led by HMS instructor Amy Roberts, MD, and director of HPCGG Raju Kucherlapati, PhD, conducted genetic analysis of over 100 children with Noonan syndrome. This large cohort of NS patients had neither PTPN11 nor KRAS mutations.

"From this group, we identified SOS1 mutations in approximately 20 percent of the cases," explains Kucherlapati, the Paul C. Cabot professor of genetics at HMS. After modeling the positions of the mutations on crystal structures of SOS1, the scientists made recombinant versions of the mutants and expressed them in mammalian cells, where it was discovered that they promoted excessive activation of RAS and its downstream target, MAP kinase, the same pathway activated by PTPN11 mutations.

"These results are the first example of activating mutations in an exchange factor in human disease," notes Neel, explaining that for families at risk for Noonan syndrome, the findings will aid in prenatal diagnosis and genetic counseling for the disorder.

"Furthermore," Neel adds, "because the other two genes that cause Noonan syndrome are also mutated in several types of leukemia and solid tumors, our findings may also expand our knowledge of cancer pathways."

Source: Beth Israel Deaconess Medical Center

Explore further: Changes in scores of genes contribute to autism risk

add to favorites email to friend print save as pdf

Related Stories

Double-teaming a whole-genome hunt

Jul 12, 2010

By inspecting the sequence of all 3 billion "letters" that make up the genome of a single person affected with a rare, inherited disorder, a Johns Hopkins and Duke University team ferreted out the single genetic mutation ...

Recommended for you

Changes in scores of genes contribute to autism risk

18 hours ago

Small differences in as many as a thousand genes contribute to risk for autism, according to a study led by Mount Sinai researchers and the Autism Sequencing Consortium (ASC), and published today in the journal Nature.

Dozens of genes associated with autism in new research

18 hours ago

Two major genetic studies of autism, led in part by UC San Francisco scientists and involving more than 50 laboratories worldwide, have newly implicated dozens of genes in the disorder. The research shows ...

Genetic link to kidney stones identified

Oct 29, 2014

A new breakthrough could help kidney stone sufferers get an exact diagnosis and specific treatment after genetic links to the condition were identified.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.