Stories about: genetics

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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Short telomeres, myriad diseases: The complex mystery of dyskeratosis congenita

dyskeratosis congenita
The chromosome tips known as telomeres can be compromised by many different mutations — with many different effects. (vitstudio/Shutterstock)

Genetic diseases largely fall into two overarching camps. You have simple, single-gene alterations that produce a single, recognizable disease. And you have conditions like diabetes or cardiovascular disease, where many variations in many genes all make small contributions that fuel the illness.

Dyskeratosis congenita (DC) doesn’t fit either profile. While this rare genetic condition manifests in certain predictable ways (bone marrow failure among the most common), there is huge variability between patients. Yet genetics has revealed one common thread: the molecular caps that protect the ends of chromosomes, known as telomeres, are shortened in DC patients. This results in cells that age too quickly.

From there things get complicated, because problems with any of 11 different genes can trigger short telomeres in DC. And DC, it appears, is only the beginning.

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Personalized medicine for kidney stones

Kidney stones

One in 10 people in their lifetime will have a kidney stone — a small, hard deposit of mineral and acid salts that can obstruct the drainage of urine, cause intense pain and, if not treated properly, lead to long-term kidney issues. Kidney stones are relatively uncommon in children, but the number of cases over the past two decades has risen.

The treatment for kidney stones has remained the same for decades — increased fluid intake, limited sodium intake, diuretics and potassium citrate therapy. Lifestyle factors are typically blamed for kidney stones, yet twin studies suggest a genetic component. In fact, new research supports pursuing a genetic diagnosis for this common condition, especially in kids.

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