This high-resolution microscope image shows the donut-shaped outer mitochondrial membranes. Unlike typical mitochondrial transporters, SLC25A46 localizes to the outer mitochondrial membrane.

CORAL GABLES, Fla. (July 13, 2015)—Researchers at the University of Miami have discovered and characterized a previously unknown disease gene linked to the degeneration of optic and peripheral nerve fibers. Their study, “Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder,” is published in the journal Nature Genetics.

Patients with mutations in this gene present symptoms similar to optic atrophy and Charcot-Marie-Tooth Type 2 (CMT2), including vision loss and weakening of the lower leg and foot muscles beginning in the first decade of life.

The novel variants occur in a gene called SLC25A46 that functions in mitochondria, organelles inside animal cells known as the “cellular engines.” They transform food into fuel that allow cells to carry out energy-demanding functions.

“Mitochondria play a large role in human health,” said Alexander Abrams, Ph.D. student in neuroscience at the Miller School of Medicine and first author of the study. “Although we study rare diseases such as CMT2 and optic atrophy, the implications encompass all forms of neurodegeneration, including Lou Gehrig’s and Parkinson’s Diseases.”

Mitochondria constantly undergo fusion and fission to respond to cellular energy demands. By changing their size and connectivity through fusion and fission, mitochondria can travel to regions in cells where they are needed.

“Our study reveals that disrupting SLC25A46 causes mitochondria to become both more highly interconnected and improperly localized in cells,” said Julia E. Dallman, assistant professor of biology in the College of Arts and Sciences and a senior author of the study. “These data support a critical role for SLC25A46 and mitochondrial dynamics in the establishment and maintenance of neuronal processes.”

SLC25A46 encodes an atypical protein in the SLC25 family. SLC25 family members act like a channel, transporting molecules across the bilayer membranes inside mitochondria. But unlike the majority of human SLC25 family members (there are 53) that transport molecules across the inner mitochondrial membrane, SLC25A46 settles on the outer mitochondrial membrane where it regulates mitochondrial dynamics.

Mutations in the genes associated with mitochondria dynamics OPA1 and MFN2 are linked to similar mitochondrial disorders. Homologous genes in baker’s yeast work in combination with a gene called UGO1, which has ancestral similarities to SLC25A46. The new findings suggest that the SLC25A46 and UGO1 proteins may play similar roles.

Given the similarities between the diseases caused by mutations in OPA1, MFN2 and SLC25A46, these genes could be involved in common pathological mechanisms of neurodegeneration, the study says.

“This finding builds on our discovery of MFN2 as a major disease gene in this area over 10 years ago,” said Stephan Züchner, professor and chair of the Dr. John T. Macdonald Foundation Department of Human Genetics, at the Miller School of Medicine, and a senior author of the study. “Only through the new genome sequencing methods and active global data exchange were we able to solve this puzzle.”

The study is a collaborative effort with investigators from nine universities and research institutions in the United States, Italy, and the United Kingdom. Coauthors from UM’s Dr. John T. Macdonald Department of Human Genetics and the John P. Hussman Institute for Human Genomics are post-doctoral fellows Adriana Rebelo and Alleene V. Strickland, graduate Michael A. Gonzalez; Ph. D. candidate Feifei Tao, Fiorella Speziani, former research project manager; Lisa Abreu, clinical research coordinator; and Rebecca Schüle, M.D., Ph.D., visiting Marie-Curie Fellow. Other Miller School co-authors are Antonio Barrientos, professor of neurology, and Flavia Fontanesi, research assistant professor in the Department of Biochemistry and Molecular Biology.

By Marie Guma-Diaz
UM News

CORAL GABLES, Fla. (May 27, 2015) – Autism Spectrum Disorder (ASD) is a neurological condition that affects approximately 2 percent of people around the world. Although several genes have been linked to multiple concurring conditions of ASD, the process that explains how specific genetic variants lead to behaviors characteristic of the disorder remains elusive.

Now, researchers are utilizing animal models to understand how dysfunction of either of two genes associated with ASD, SYNGAP1 and SHANK 3, contributes to risk in ASD. The new findings pinpoint the actual place and time where these genes exert influence in brain development and function. The findings are published in the journal Human Molecular Genetics.

“The overall goal of our study was to generate and directly compare two zebrafish models of ASD and to gain an in vivo perspective on how ASD genetic variants impact neural circuit development in embryos,” said Julia E. Dallman, assistant professor of biology at the University of Miami’s College of Arts and Sciences and lead investigator of the study. “Our work begins to address a major gap in our current understanding of ASD.”

The findings show that disrupting the expression or “knocking down” either SYNGAP1 or SHANK 3 genes affects early brain development in the mid- and hind-brain regions and results in hyper-excitable behaviors.

“It is well known that genetics plays a significant role in ASD risk and that many genes are involved, but the exact nature of their involvement is not well understood,” said Margaret A. Pericak-Vance, director of the John P. Hussman Institute for Human Genomics, the Dr. John T. Macdonald Foundation Professor of Human Genetics, at the UM Miller School of Medicine, and co-author of the study. “The implications of the present study are important as it helps us understand how two ASD-related genes, SHANK3 and SYNGAP1, contribute to the development of the disorder.”

The study is titled: “Two knockdown models of the autism genes SYNGAP1 and SHANK3 produce similar behavioral phonotypes associated with embryonic disruptions of brain morphogenesis.”

In contrast to previous studies of ASD-linked genes in humans and mice, the current study is conducted in developing zebrafish because zebrafish embryos are transparent organisms that develop outside the mother, thus allowing the researchers to observe early brain development in the fish.

The researchers chose to analyze SYNGAP1 and SHANK3 orthologs—genes in different species that have a common ancestor and maintain the same function—since embryonic functions of these ASD-linked genes are unknown.

The study utilized three groups of fish. In two of the groups, the expression of either SYNGAP 1 or SHANK 3 genes was knocked down by injecting a molecule that specifically targets each gene. The third was also injected with a similar molecule, but with no match in the zebrafish genome, so it functioned as a control group. The behavior of larvae in all groups was analyzed by studying their escape responses in the presence of a stimulus.

The experiments showed that while control larvae swam away from the stimulus, the knock-down larvae had unproductive escape responses, as well as significantly reduced swimming velocities.

Moreover, a subset of the knock-down larvae exhibited spontaneous seizure-like behaviors, and there were significant changes in the brain structure of these larvae, indicative of delayed development.

Together these findings support the emerging opinion that mutations of specific ASD-related genes disrupt early embryogenesis and that these early disruptions play a key role in the development of the disorder.

The team is now working to determine exactly how early developmental deficits impact later behaviors. In the long-term, they hope to use SYNGAP1 and SHANK3 zebrafish models for drug screening, to identify environmental risk factors, and test potential therapies for ASD.

This work was supported by an NIH grant from the National Institutes of Mental Health to Julia Dallman and by funding from both the Seaver Foundation to Joseph Buxbaum and the John P. Hussman Foundation to Margaret Pericak-Vance.

Robert A. Kozol, graduate research assistant in the UM Department of Biology is first author of the study. Other coauthors from the UM Department of Biology are: James D. Baker, research assistant professor, and Bing Zou, graduate student. From the UM John P. Hussman Institute for Human Genomics: Eden R. Martin, professor of human genetics and public health sciences; Michael L. Cuccaro, professor of human genetics and psychology; John R. Gilbert, professor of human genetics; Holly N. Cukier, assistant scientist; Vera Mayo, research associate; Anthony J. Griswold, associate scientist, and Patrice L. Whitehead, research laboratory director.

From The Seaver Autism Center for Research and Treatment Department of Psychiatry, Friedman Brain Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai: Silvia De Rubeis, postdoctoral fellow; Guiqing Cai, clinical molecular genetics fellow; and Joseph D. Buxbaum, professor of psychiatry, neuroscience, genetic and genomic sciences; and from the Department of Epidemiology and Biostatistics, Institute for Computational Biology, Case Western Reserve University School of Medicine: Jonathan L. Haines, professor and chair of the department of epidemiology.

Byron Lam and Rong Wen, professors of ophthalmology at Bascom Palmer, discovered a key marker in blood and urine that can identify people who carry genetic mutations in a gene responsible for retinitis pigmentosa.

Research led by physician-scientists at Bascom Palmer Eye Institute has produced a breakthrough discovery in diagnosing retinitis pigmentosa, a blinding disease that affects about 1 in 4,000 people in the United States. Read the full story

Margaret Pericak-Vance, third from left, with members of the Hussman Institute’s outreach team, from left, Larry Deon Adams, Doris Caldwell, and Krystal Murphy.

Researchers at the Miller School of Medicine have collaborated with a national team to identify a new gene associated with Alzheimer’s disease in African Americans. Published April 10 in the prestigious Journal of the American Medical Association, their study, “Variants in the ATP-binding cassette transporter, ABCA7, and the apolipoprotein E ε4 allele substantially and equally influence risk of late-onset Alzheimer’s disease in African Americans,” provides new directions for biological, genetic, and therapeutic studies of Alzheimer’s disease. Read the full story

From left are William K. Scott, Margaret Pericak-Vance, Stephen G. Schwartz, and Jaclyn L. Kovach.

Researchers from the Miller School of Medicine collaborated with an international team to identify seven new genes associated with age-related macular degeneration (AMD), the most common form of vision loss in older people. Published online March 3 in Nature Genetics, their study, “Seven New Loci Associated with Age-Related Macular Degeneration,” provides new directions for biological, genetic, and therapeutic studies of macular degeneration. Read the full story