Summary: Researchers have discovered a new gene linked to a form of syndromic autism and uncovered how its mutation can contribute to the condition.
Source: Institute of Science and Technology Austria
An international research team led by IST Austria scientists has identified a new genetic cause of syndromic autism; the study was published in Cell.
Autism spectrum disorders (ASD) affect about one percent of people worldwide and present a broad range of challenges in social interaction and communication. In a study published in Cell, a team led by Gaia Novarino, Professor at IST Austria, reports the discovery of a new autism-associated gene and reveals the mechanism by which its mutation leads to neurological dysfunction. Novarino emphasizes the importance of this work: “Autism is genetically diverse—many causative mutations are individually rare, which complicates the development of tailored therapies. Our study not only identifies SLC7A5 as a new autism-linked gene, but it also explains how disruption of this gene alters brain chemistry and neuronal function. Importantly, other autism-associated genes appear to share this same mechanism, suggesting a definable subgroup of ASDs.”
Ahmet Okay Caglayan, Chairman of the Department of Medical Genetics at Istanbul Bilim University and a co-author, notes how collaboration enabled the discovery: “Finding new genes in heterogeneous diseases such as autism is challenging. Through an international collaborative effort, we detected damaging mutations in SLC7A5 in several patients born to consanguineous parents who were diagnosed with a syndromic form of autism.”
SLC7A5 is a transporter that moves large neutral amino acids into the brain, including branched-chain amino acids (BCAAs). To determine how loss of SLC7A5 function causes neurological features associated with ASD, researchers created mice lacking Slc7a5 specifically at the blood–brain barrier. These mutant mice show reduced brain levels of BCAAs, disrupted protein synthesis in neurons, and altered gene translation—changes that correlate with impaired social behaviors and other neurobehavioral abnormalities commonly observed in autism models.
These findings build on earlier work from Novarino’s group, which linked defects in BCAA breakdown to ASD, intellectual disability and epilepsy in other patients. Together, the studies indicate that disruption of BCAA homeostasis—whether by impaired transport into the brain or by defective catabolism—can produce overlapping neurological outcomes. Novarino cautions that not all forms of autism involve amino-acid disturbances and that SLC7A5-related syndromes are rare, but the overlap in mechanisms suggests that several distinct genetic causes may converge on common metabolic pathways.
Crucially, the research team demonstrated partial reversibility of some deficits in adult Slc7a5-deficient mice. When BCAAs were administered directly into the brain for three weeks, several behavioral abnormalities improved. Dora Tărlungeanu, the study’s first author, highlights the therapeutic implications while urging caution: “Our preclinical results identify a potential intervention for certain symptoms in mice, but translating this into a safe and effective human therapy will require many more years of careful research.” Although intracerebral amino-acid delivery as used in mice is not a practical or immediate option for patients, the study challenges the view that all autism-related neurological changes are permanently fixed and suggests that metabolic restoration could be a viable route for treatment development in specific cases.
Source: Elisabeth Guggenberger, Institute of Science and Technology Austria
Original research: “Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder” by Dora C. Tărlungeanu et al., Cell. Published online December 1, 2016 (doi:10.1016/j.cell.2016.11.013)
Highlights
- SLC7A5 is essential to maintain normal brain levels of branched-chain amino acids (BCAAs).
- Loss of SLC7A5 at the blood–brain barrier produces a distinctive brain amino-acid profile and disrupts neuronal protein synthesis and mRNA translation.
- Patients with deleterious SLC7A5 mutations present with syndromic autism and motor delays.
- Behavioral deficits in Slc7a5-deficient mice can be partially rescued by intracerebral BCAA administration, indicating potential reversibility of some symptoms.
Summary
Autism spectrum disorders encompass genetically diverse conditions that often overlap with other neurological syndromes. This study identifies SLC7A5, a transporter at the blood–brain barrier, as a critical regulator of brain BCAA levels. In mice, endothelial deletion of Slc7a5 leads to abnormal brain amino-acid composition, altered mRNA translation, and pronounced neurobehavioral deficits. Multiple patients carrying homozygous, damaging SLC7A5 mutations exhibit autistic traits and motor impairment, defining a recognizable clinical syndrome. Experimental restoration of brain BCAA levels alleviates some behavioral abnormalities in adult mutant mice, supporting an essential role for BCAAs in human brain function and revealing a metabolic pathway that could guide future targeted therapies for a subgroup of ASDs.
This article summarizes published research and does not provide medical advice. Further clinical research is required before any experimental interventions based on these findings can be considered for human patients.