Stories about: genetics

Two resilient dogs point to new targets for Duchenne muscular dystrophy

Duchenne muscular dystrophy protective genes
Suflair, at right, is alive and well at 11 years despite having the DMD mutation (courtesy Natássia Vieira)

Two golden retrievers that had the genetic mutation for Duchenne muscular dystrophy (DMD), yet remained healthy, have offered up yet another lead for treating this muscle-wasting disorder.

For several years, Natássia Vieira, PhD, of the University of São Paolo, also a fellow in the Boston Children’s Hospital lab of Louis Kunkel, PhD, has been studying a Brazilian colony of golden retrievers. All have the classic DMD mutation and, as expected, most of these dogs are very weak and typically die by 2 years of age. That’s analogous to children with DMD, who typically lose the ability to walk by adolescence and die from cardiorespiratory failure by young adulthood.

But two dogs appeared unaffected. Both ran around normally. The elder dog, Ringo, lived a full lifespan, and his son Suflair is still alive and well at age 11.

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Science then & now: Progress that you can see

Click and drag to compare and contrast archive photos from the lab with current-day images of research at Boston Children’s Hospital.

Then, 1986: Stuart H. Orkin, MD, examines the DNA sequence of a gene.

Now, 2017: Today, Orkin is associate chief of Hematology/Oncology and chairman of Pediatric Oncology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center (DF/BC). In this photo, he examines a rendering of a gene regulatory molecule’s structure. Orkin’s lab investigates gene regulation of stem cell development, genetic vulnerabilities to cancer and gene and other therapies for treating hemoglobin disorders. 

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Discovering a rare anemia in time to save an infant’s life

Illustration of the erythropoietin hormone. A newly-discovered genetic mutation, which switches one amino acid in EPO's structure, resulted in two cases of rare anemia.
An illustration showing the structure of a cell-signaling cytokine called erythropoietin (EPO). It has long been thought that when EPO binds with its receptor, EPOR, it functions like an on/off switch, triggering red blood cell production. New findings suggest that this process is more nuanced than previously thought; even slight variations to cytokines like EPO can cause disease.

While researching a rare blood disorder called Diamond-Blackfan anemia, scientists stumbled upon an even rarer anemia caused by a previously-unknown genetic mutation. During their investigation, the team of scientists — from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, the Broad Institute of Harvard and MIT and Yale University — had the relatively unusual opportunity to develop an “on-the-fly” therapy.

As they analyzed the genes of one boy who had died from the newly-discovered blood disorder, the team’s findings allowed them to help save the life of his infant sister, who was also born with the same genetic mutation. The results were recently reported in Cell.

“We had a unique opportunity here to do research, and turn it back to a patient right away,” says Vijay Sankaran, MD, PhD, the paper’s co-corresponding author and a principal investigator at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. “It’s incredibly rewarding to be able to bring research full circle to impact a patient’s life.”

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Science Seen: Disrupted developmental genes cause ‘split brain’

split brain syndrome
The two halves of the brain on the right, from a patient with the DCC mutation, are almost completely disconnected. The mutation — first recognized in worms — prevents axons (nerve fibers) from crossing the midline of the brain by interfering with guidance cues. Image courtesy Ellen Grant, MD, director, Fetal-Neonatal Neuroimaging and Developmental Science Center.

Tim Yu, MD, PhD, a neurologist and genomics researcher at Boston Children’s Hospital, was studying autism genes when he saw something on a list that rang a bell. It was a mutation that completely knocked out the so-called Deleted in Colorectal Carcinoma gene (DCC), originally identified in cancer patients. The mutation wasn’t in a patient with autism, but in a control group of patients with brain malformations he’d been studying in the lab of Chris Walsh, MD, PhD.

Yu’s mind went back more than 20 years. As a graduate student at University of California, San Francisco, he’d conducted research in roundworms, studying genetic mutations that made the worms, which normally move in smooth S-shaped undulations, move awkwardly and erratically.

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Why I’m tall and you’re short: GIANT effort finds rare, potent height genes

height genes that make us tall or short

Height is the “poster child” of complex genetic traits, meaning that it’s influenced by multiple genetic variants working together. Because height is easy to measure, it’s a relatively simple model for understanding traits produced by not one gene, but many.

“Mastering the complex genetics of height may give us a blueprint for studying multifactorial disorders that have eluded our complete understanding, such as diabetes and heart disease,” says Joel Hirschhorn, MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard.

Hirschhorn chairs the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, an international group that’s just probed more deeply into the genetics of height than ever before. Its findings, reported today in Nature, reveal previously unknown biological pathways tied to height.

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Seeking a way to keep organs young

Images of mouse hearts with fibrosis
These mouse hearts show differing levels of fibrosis (blue) resulting from cardiac stress. New Boston Children’s Hospital research suggests certain therapies could prevent or reduce fibrosis, like we see in the center and right images.

The wear and tear of life takes a cumulative toll on our bodies. Our organs gradually stiffen through fibrosis, which is a process that deposits tough collagen in our body tissue. Fibrosis happens little by little, each time we experience illness or injury. Eventually, this causes our health to decline.

“As we age, we typically accumulate more fibrosis and our organs become dysfunctional,” says Denisa Wagner, PhD, the Edwin Cohn Professor of Pediatrics in the Program in Cellular and Molecular Medicine and a member of the Division of Hematology/Oncology at Boston Children’s Hospital and Harvard Medical School.

Ironically, fibrosis can stem from our own immune system’s attempt to defend us during injury, stress-related illness, environmental factors and even common infections.

But a Boston Children’s team of scientists thinks preventative therapies could be on the horizon. A study by Wagner and her team, published recently by the Journal of Experimental Medicine, pinpoints a gene responsible for fibrosis and identifies some possible therapeutic solutions.

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Human brain evolution holds clues about autism… and vice versa

human brain evolution autism Human Accelerated Regions
Humans evolved to become more social and cognitively advanced, thanks to genetic changes in regions such as HARs — the child with autism spectrum disorder (ASD) being the exception. While mutations in protein-coding genes continue to be explored in ASD (indicated by the red ribbon of RNA), the scientists at far left are suggesting that mutations in regulatory elements (the histones , in green, and their modifications shown in yellow) may be important in both ASD and human evolution. (Illustration: Kenneth Xavier Probst)

Starting in 2006, comparative genomic studies have identified small regions of the human genome known as Human Accelerated Regions, or HARs, that diverged relatively rapidly from those of chimpanzees — our closest living relatives — during human evolution.

Our genomes contain about 2,700 HAR sequences. And as reported today in Cell, these sequences are often active in the brain and contain a variety of mutations implicated in autism and other neurodevelopmental disorders.

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The genetics of early-onset psychosis: Could it aid understanding of schizophrenia?

psychosis schizophrenia
(Thomas Zapata/Wikimedia Commons)

At age six, Matthew (not his real name) began hearing voices coming out of the walls and the school intercom, telling him to hurt himself and others. He saw ghosts, aliens in trees and color footprints. Joseph Gonzalez-Heydrich, MD, a psychiatrist at Boston Children’s Hospital, put Matthew, at age 9, on antipsychotic medications, and the hallucinations stopped.

It’s rare for children so young to have psychotic symptoms. Intrigued, Gonzalez-Heydrich referred Matthew for genetic testing.

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Science Seen: Worms give a clue to how the nervous system stays organized

nervous system tiling
Courtesy Candice Yip

To the eye, nervous systems look like a tangled mess of neurons and their tree-like branches known as dendrites, but it’s really organized chaos. How the system finds order has intrigued but eluded scientists. In the worm C. elegans, Max Heiman, PhD and graduate student Candice Yip found an elegant system to help explain how neurons each maintain their own space.

Normally, worms have just one neuron of a certain type on either side of their bodies. Yip did a “forward genetic screen” — mutating genes at random to find factors important for neuron wiring. One mutation caused the worm to grow not one set of neurons but five. By engineering the neurons to make a color-changing signal — as shown above — Yip showed that these extra neurons didn’t overlap with each other, but instead carved out discrete territories — a phenomenon known as tiling. How?

Acting on a hunch, Yip and Heiman, of Harvard Medical School and Boston Children’s Hospital’s Division of Genetics and Genomics, showed that C. elegans, faced with an increase in neurons, pressed a molecule called netrin into service to enforce boundaries between them. Netrin is better known for helping nerve fibers navigate to their destinations. When Yip took netrin out of action, the dendrites from the five neurons crossed the invisible borders and grew entangled.

The findings, published today in Cell Reports, could provide insight into neuropsychiatric diseases, believes Heiman, also part of Boston Children’s F.M. Kirby Neurobiology Center. “It’s fundamental to neuropsychiatric disease to make sure brain wiring goes right,” he says. “This is also story about how new features evolve, and how you can form something as complicated as a nervous system. There are pathways that bring everything into order.”

Read more in this feature from Harvard Medical School and learn more about Heiman’s research.

 

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Expectation vs. reality: Rare disease parents’ mixed feelings about genetic research results

rare disease genetic resultsTypically, when you enroll in a study, it’s not with the expectation that you will receive results. In genomics studies, it’s becoming common to give families the option to get individual results — the newborn sequencing study, Baby Seq, is just one example — as an incentive to participate. Families of children with rare disease, especially undiagnosed illnesses, need no incentive: they’re desperate for answers.

But how do families actually feel once they get genetic results? We conducted interviews with nine rare disease parents (six mothers, three fathers) whose children were enrolled at the hospital’s Manton Center for Orphan Disease Research. What we found is more complexity than we expected.

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