Human Genetics Archives - Sanford Burnham Prebys
Institute News

Soft bone disease research — from bench to bedside and back

Authorjmoore
Date

April 7, 2016

Funding for the laboratory of José Luis Millán, PhD, professor in the Human Genetics Program, has been renewed by the NIH to the tune of $3 million over the next five years. The grant ensures that they can continue to advance understanding of and develop treatments for the rare disease called hypophosphatasia (HPP). This disease—also known as soft bones—can cause skeletal deformities of the limbs and chest and result in frequent fractures and premature loss of teeth. HPP is estimated to affect approximately one per 100,000 live births. Continue reading “Soft bone disease research — from bench to bedside and back”

Institute News

Closing in on the causes of Alzheimer’s disease

AuthorGuest Blogger
Date

April 5, 2016

This post was written by Nicole Le, a guest blogger.

Imagine if we could clear the brain of plaque that accumulates and causes Alzheimer’s disease (AD) as simply as having the plaque removed from our teeth? The body has a natural clearing mechanism in place to rid the brain of these deposits, but if this mechanism gets overwhelmed or disrupted, the plaques can accumulate and lead to neurodegeneration. Continue reading “Closing in on the causes of Alzheimer’s disease”

Institute News

Study triples the number of known cases of a rare disease

Authorjmoore
Date

March 10, 2016

A recent paper from the laboratory of Hudson Freeze, PhD, characterizes 39 previously unreported cases of a specific type of congenital disorder of glycosylation (CDG). CDGs, the focus of research in Freeze’s lab in SBP’s Sanford Children’s Health Research Center, are rare inherited disorders. CDG symptoms, which can include developmental delay, movement problems, and impaired function of multiple organs, differ depending on the underlying mutation. Continue reading “Study triples the number of known cases of a rare disease”

Institute News

Rare Disease Day symposium brings together experts on disorders of glycosylation

Authorjmoore
Date

March 2, 2016

The Rare Disease Day symposium on February 26-27 featured many fascinating talks from experts on numerous aspects of congenital disorders of glycosylation (CDGs), from fundamental work on glycosylation pathways to animal models to diagnosis in the clinic. Following are summaries of each presentation:

Lawrence Tabak, D.D.S, PhD, deputy director of the NIH—After presenting his research on glycosylating enzymes in the 1980s, which helped lay the foundation for understanding the processes that are impaired in CDGs, Tabak discussed several initiatives by the NIH, including the Precision Medicine Initiative and efforts to increase reproducibility.

William Gahl, MD, PhD, director of the National Human Genome Research Institute (NHGRI)—Gahl highlighted several successes of the Undiagnosed Diseases Program. Most relevant to the field of CDGs was the discovery of the gene underlying a new type of CDG, in which an enzyme responsible for generating a necessary precursor for protein glycosylation (uridine diphosphate) is inactivated. This work also found that supplementation with uridine was an effective therapy.

Shengfang Jin, PhD, scientist at Agios Pharmaceuticals Inc.Jin presented her work on a mouse model of PMM2-CDG, which is caused by mutations in the gene for phosphomannomutase 2. Her research has identified a promising biomarker for PMM2-CDG, which is one of the more common types of CDG.

Richard Steet, PhD, associate professor at the University of Georgia—Steet’s lab is developing a new method of identifying which proteins are glycosylated by particular enzymes, which is important for understanding how each CDG-associated mutation leads to disease.

Reid Gilmore, PhD, professor at University of Massachusetts Medical School—Gilmore gave a detailed view of how two CDG-associated mutations, in isoforms of the same component (STT3A and STT3B) of a major glycosylating enzyme, oligosaccharyltransferase, impair protein glycosylation.

Robert Haltiwanger, PhD, professor at the University of Georgia—In another presentation on fundamental glycobiology, Haltiwanger described the function of two enzymes in the same pathway (fucosylation) inactivated in certain CDGs. Mutations in these enzymes underlie Peters plus syndrome and a single case of an unnamed severe CDG, respectively.

Marjan Huizing, PhD, staff scientist at the NHGRI—Using a mouse model of GNE myopathy, a progressive muscle disease caused by mutations in an enzyme required for protein sialylation, Huizing’s lab identified a therapy, supplementation with the sugar ManNAc, which is now in phase 2 trials, and identified a key biomarker. The mouse model also suggested that sialylation problems may be associated with certain kidney diseases, which is now under investigation.

Raymond Wang, MD, clinical geneticist at CHOC Children’s Clinic—Wang told the story of how he and scientific collaborators diagnosed an unusual case that initially appeared to be a CDG because of abnormal glycosylation. The disease-causing mutation was finally identified to be in mitochondrial translation, highlighting the similarities between CDGs and mitochondrial diseases.

David Beeson, PhD, professor at the University of Oxford—Beeson described a subset of congenital myasthenias caused by mutations in glycosylating enzymes, which have distinct symptoms from other myasthenias. These mutations likely cause this disorder by selectively impairing processing of the receptor by which muscle cells receive signals from nerves—the nicotinic acetylcholine receptor.

Lance Wells, PhD, professor at the University of Georgia— Wells summarized his work on the molecular basis of dystroglycanopathies, a subgroup of muscular dystrophies that arise from defects in O-mannosylation enzymes. Most recently, his lab resolved the puzzle of how mutations in an enzyme involved in a different form of glycosylation could cause this disease—they showed that the enzyme’s function had been incorrectly assigned.

Taroh Kinoshita, PhD, professor at Osaka University—Kinoshita is an expert on the addition of sugar-based anchors to lipids (GPI anchors), which link many proteins to the cell surface. He presented some of the extensive work from his team on how mutations in GPI-synthesizing enzymes cause disease, including identification of a therapy, vitamin B6, for seizures in GPI deficiencies.

Eva Morava, MD, PhD, professor at Tulane University Medical Center and the University of Leuven—Morava described preliminary results of a clinical trial of galactose supplementation to treat PGM1-CDG, in which patients are deficient in phosphoglucomutase-1 (this also impairs glucose metabolism). In these patients, galactose improves liver function and endocrine abnormalities and normalizes clotting factors.

Lynne Wolfe, MS, C.N.R.P. clinical research coordinator at the NHGRI—Wolfe discussed the CDG natural history study underway at the NIH—its goals and progress so far. The findings of this study will serve as a resource both for future diagnoses and for researchers in the field to correlate pathways with symptoms.

Tadashi Suzuki, D.Sci., team leader at the RIKEN Global Research Cluster—NGLY1 is different from other CDG-associated genes—it encodes a deglycosylating enzyme, which helps degrade glycosylated proteins that aren’t properly folded. Suzuki’s team has shown that inhibiting another deglycosylating enzyme, ENGase, prevents the formation of aggregates of misfolded proteins, suggesting that it could be a therapeutic target.

Hamed Jafar-Nejad, MD, associate professor at Baylor College of Medicine—Using fruit flies as a model, Jafar-Nejad’s lab is investigating how NGLY1 deficiency affects development. These flies replicate many of the features of human disease, including growth delay and impaired movement, so they could yield important insights into pathogenesis.

Institute News

Fiona Waddell embraces Rare Disease Day as a patient and advocate

AuthorGuest Blogger
Date

February 12, 2016

On February 26-27, 2016, Hudson Freeze, PhD, director of SBP’s Human Genetics Program, will lead the 7th annual Rare Disease Day Symposium at SBP. With the theme of human glycosylation disorders, the event will unite researchers, clinicians, patients and advocates to find better diagnostics, treatments and maybe even cures for people like Fiona Waddell, a CDG patient.  Continue reading “Fiona Waddell embraces Rare Disease Day as a patient and advocate”

Institute News

New marker can help sick kids

Authorsgammon
Date

January 12, 2016

There are more than 7,000 rare diseases, but congenital disorders of glycosylation (CDGs) are among the cruelest. One particular condition, called ALG1, can have dire consequences. Affected children face intellectual disabilities, seizures, skeletal issues, facial deformities and many other problems.

“These are really sick kids,” says Hudson Freeze, PhD, professor and director of the Human Genetics Program at SBP. “Almost 45 percent die in the first several years, and many of these children will have severe developmental delays.”

Glycosylation is a critical biological process, in which sugar molecules are added to proteins to make them function properly. A protein that’s improperly glycosylated is like a car without a steering wheel – it simply can’t perform its job.

To make matters worse, correctly diagnosing ALG1 and other CDGs can be a long, stressful and expensive process. Sometimes families must wait months or years to find out what’s causing their child’s condition. And while genomic sequencing is beginning to make a difference, more must be done to diagnose sick kids and help parents make informed decisions.

One potential solution is disease markers – biochemical signatures that identify particular conditions. Armed with this information, clinicians could accelerate the diagnostic process with a simple blood test.

A Unique Sugar Molecule

Researchers may have found a marker for ALG1 and possibly other CDGs. In a paper published in the journal Clinical Chemistry, the team describes a unique sugar molecule that is particularly common in children with ALG1.

The sugar, a type of N-tetrasaccharide, was discovered by Miao He, PhD, who co-directs the Metabolic Disease Laboratory at The Children’s Hospital of Philadelphia. However, he had only a few patients and she was unclear on the molecule’s origin. Working closely with Freeze’s lab, she started hunting for the aberrant sugar in Freeze’s large collection of proven ALG1 patients.

“We looked at a number of kids with ALG1 and kept finding this abnormal sugar,” says Freeze. “It’s a sugar chain that doesn’t normally exist in nature. You can perform a very simple test, that costs just a few hundred dollars, and if you see this abnormality, you could get genetic confirmation and turn it around quickly.”

The beauty of this marker is that it narrows the field for genomic analysis. Rather than looking at a patient’s entire genome – billions of base pairs and more than 20,000 genes – clinicians can focus on the gene that may be causing the disorder, dramatically accelerating the diagnostic process.

Quickly diagnosing a rare disorder can help get kids into treatment, if treatments are available. But it can also help parents navigate the family planning process and inform prenatal testing. In the big picture, disease markers could be a critical adjunct for genomic testing.

“Genome and exome sequencing is the future, but it will require some biochemical confirmation to support the genomic test,” notes Freeze. “This marker can really help us shortcut the long diagnostic odyssey many parents must go through.”

Institute News

Run Noah run

Authorsgammon
Date

July 1, 2015

On Saturday, July 4, at 3 p.m., an extraordinary man named Noah Coughlan will complete a run—a solo run— that stretched more than 3,000 miles and 13 states. His journey will have lasted 127 days. Even more impressive is that this is the third time he has done it. Why on earth would someone take on such a feat? Continue reading “Run Noah run”

Institute News

Stem cell model reveals molecular cues critical to neurovascular unit formation

Authorsgammon
Date

June 1, 2015

Crucial bodily functions we depend on but don’t consciously think about — things like heart rate, blood flow, breathing, and digestion — are regulated by the neurovascular unit. The neurovascular unit is made up of blood vessels and smooth muscles under the control of autonomic neurons. Yet how the nervous and vascular systems come together during development to coordinate these functions is not well understood. Using human embryonic stem cells, researchers at Sanford-Burnham, University of California, San Diego School of Medicine, and Moores Cancer Center created a model that allows them to track cellular behavior during the earliest stages of human development in real-time. The model reveals, for the first time, how autonomic neurons and blood vessels come together to form the neurovascular unit. The study was published May 21 by Stem Cell Reports. Continue reading “Stem cell model reveals molecular cues critical to neurovascular unit formation”

Institute News

Rare Disease Day gathers patients, clinicians, and researchers to discuss sugar therapy

Authorsgammon
Date

March 2, 2015

“Treating Disease with Sugar” was the theme of this year’s Annual Rare Disease Day Symposium at Sanford-Burnham, a subject that drew scientists and patients together in an informal setting to share promising research on how sugar may be used to treat certain rare genetic disorders—and some not-so-rare disorders. While sugar may seem like an odd approach, for patients with mutations in the genes that attach sugar molecules to proteins (glycobiology), and sufferers of multiple sclerosis and cancer, the concept is proving both rational and effective. Continue reading “Rare Disease Day gathers patients, clinicians, and researchers to discuss sugar therapy”