Though most people expect a baby to bring profound changes to his parents, few expect him to launch a 14-year-old cousin's career. But the birth of Hiba Risheg's cousin, Zied, led to a breakthrough career in genetics.
Zied was born with tuberous sclerosis complex (TSC), a genetic disorder characterized by developmental delay or mental retardation, seizures, and lesions of the skin and nervous system.
"We'd never heard of TSC before or had anyone in the family with any form of seizures," says Risheg, '97 BS Biological Sciences, in her laboratory office. "My mother and I started researching it. It was an eye-opener."
The experience prompted her parents, Samira and Mohammed Risheg, to seek graduate degrees and work with children just like Zied in the Clark County School District. Their daughter, however, took a different approach. She wanted to understand the genetics behind the disorder. Years later, she has her answer. TSC can be inherited, but most often results from a spontaneous genetic mutation. "It's something that just happens. Just by chance," Risheg says.
But in searching for answers for her family, Risheg has found answers for a number of other families. In April, she was credited with discovering the gene that causes a form of mental retardation called FG syndrome. It's a breakthrough for scientists and families who have been searching for the gene responsible for the condition for more than 40 years.
Sequence of Events
At 29, Risheg has accomplished more than
most people twice her age. She started at UNLV at the remarkable age of 16 while
living at home. As an undergrad, she
admits, "I wasn't the best at genetics in
college. I initially had trouble relating it to
human genetics." By 18, she had finished
her undergraduate degree in cellular and
molecular biology with a minor in chemistry.
The following year, she stayed at
UNLV in the biological sciences master's
program. That year was an important one
for her.
She began teaching students under the guidance of her mentor, biological sciences professor Roberta Williams. The experience is one that was both comical and enlightening.
"Most students were older than me. I think they were stunned," she says, smiling. "But that experience shaped me. I wanted to teach. I wanted everyone to be as excited about biology as I was." A year later she was ready to leave the comfort of Las Vegas for the University of Alabama at Birmingham's doctorate program in medical genetics, where she spent the next four and a half years. She began to catch up to her peers in age. But still, she didn't fit the mold of a staid researcher. "I was giggly, and I wanted to mess around in the lab," she remembers with a laugh.
Then, she landed at the Greenwood Genetic Center in South Carolina for a post-doctoral fellowship. The nonprofit institute provides clinical services, conducts research, and trains individuals with medical or doctorate degrees seeking specialized academic, clinical, and research careers in human and medical genetics.
Risheg focused on two areas of study — clinical cytogenetics (the study of chromosomes and the diseases that result from structural abnormalities) and molecular genetics (the branch of genetics that deals with the expression of genes by studying DNA sequences). The difference between the two areas is one of degrees. A single band on a chromosome contains hundreds of genes. "Molecular genetics is as small and as exact as you can get. You're looking for a change in gene sequence."
Center directors were interested in HOPA/MED12, a gene on the Xq13 chromosome suspected of being related to mental retardation. But sequencing the very large gene would be months of tedious work. When no one else stepped forward, Risheg volunteered. "Scientists have been looking at this gene for years but no complete sequencing has been done on a population of mentally retarded individuals — mostly because of the breadth of the undertaking."
During the year she spent on that one gene, she admits she sometimes wanted to move on to something else. The work was tedious, though. Why can't I get myself a fun job, she wondered to herself. After all, no one else had had luck with that gene. In the quiet of the lab, she used to joke with herself: "Hiba HOPA she finds a mutation."
"It's like you're on a hunt. So I sequenced, I sequenced, I sequenced." Then, with just three months left in the fellowship, she found it.
Two samples showed the same sequencing change and analysis yielded an apparent link between a base change (R9261W) within the gene of two males with mental retardation and FG syndrome. FG syndrome is an Xlinked form of mental retardation first described in 1974 in five related males with mental retardation, relatively large heads, diminished muscle tone, and certain facial characteristics.
Then she located five additional FG syndrome families with the same R961W mutation in HOPA/ MED12. The next step was to test samples from the general population.
"No one in the general population had it. I did over a thousand samples." That's when her fellow researchers got excited. "It's big from a genetics standpoint."
Her findings were quickly confirmed in conjunction by scientists at the Greenwood Genetic Center and at other institutions in the United States and Europe. In April, the research was published in the academic journal Nature Genetics.
With the causative gene isolated, the syndrome can be better defined and diagnostic testing can be offered. All the families that are known to have FG were invited to Greenwood Genetic Center to be re-evaluated and tested this spring. Their blood samples will be important as scientists begin studies on how the mutation alters gene function and affects the protein.
With all the attention the discovery is getting, Risheg is modest about her role. "It's not just about how smart you are," she says. "It's about how determined you are to finish."
Life After Research
Six months ago, Risheg became clinical
cytogenetics laboratory director at
GeneCare Medical Genetics Center in
Chapel Hill, N.C.
She oversees an 18-member laboratory staff that primarily conducts prenatal chromosome analyses and molecular testing. Her lab grows cells from an amniocentesis, looks at the chromosomes, and determines if a syndrome is present. They also do chromosome analysis on people who already have a chromosomal translocation and worry about passing that on to their future children.
"In graduate school, you're so busy doing the work you don't realize how important it is until you're actually in the seat and signing someone's report. People's decisions are based on what you see."
Risheg pulls out a gel sheet of chromosome types and points to various pairs and talks about what they are looking for. She patiently explains how chromosomes contract and expand and how that sometimes affects what shows up on the DNA sample.
"You need to make sure you're the best at what you do, so that at the end of the day you're not going home worried about a sample."
The desire to teach is still under the surface. She started a monthly "let's get together and talk about a syndrome" group and strives to be accessible to her staff.
She enjoys that where she works provides a service to people. And it's a place that allows her the freedom of life after hours in a way that academia would not. But after the experience of making a genetic discovery, research may not be completely out of her future.
"It's a very sweet reward. I'm proud of myself for sticking with it."
