Stephen G. Kaler, M.D.

Senior Investigator

Section on Translational Neuroscience


35A 2D971


Research Topics

Mechanisms of and Remedies for Neurometabolic Disorders

The Kaler Laboratory is committed to identifying genetic causes for copper transport diseases, understanding how the responsible genes participate in neurologic processes, dissecting disease mechanisms, and using this knowledge to improve health through rational treatments, including gene therapy. Patients and families affected by inherited neurometabolic disorders provide the impetus for scientific inquiry. In addition to molecular genetics, the laboratory employs model organisms (yeast, mouse, zebrafish), cellular, biochemical, and biophysical approaches, and human clinical trials. Cerebrospinal fluid-directed adeno-associated virus (AAV) gene therapy for Menkes disease and lysosomal storage diseases represent our current main directions. Using biochemical and cell biological techniques, we are also working to distinguish the mechanisms responsible for normal copper transport activity and intracellular trafficking of ATP7A and ATP7B, closely related copper-transporting ATPases.


Stephen Kaler completed his undergraduate studies at Boston College and received a M.D. from the University of Rochester (NY). He obtained clinical training in internal medicine and pediatrics in Boston before coming to NIH for fellowship in medical genetics and became board-certified in clinical genetics, biochemical genetics, and molecular genetics. He identified the molecular basis for the copper transport disorder occipital horn syndrome (Nature Genetics 8:195-202, 1994) and, with international collaborators, delineated several other conditions affecting copper homeostasis. These include ATP7A-related isolated distal motor neuropathy (Am J Hum Genet 86:343-352, 2010), and unique syndromes caused by mutations in SLC33A1, an acetylCoA transporter (Am J Hum Genet 90:61–68, 2012), and CCS, a copper chaperone (Hum Mutat 33:1207-1215, 2012). His laboratory illuminated the mechanisms underlying ATP7A–related motor neuron degeneration, establishing a link between genetically distinct forms of motor neuron disease, and highlighting the role of ATP7A in the peripheral nervous system (Hum Mol Genet 21:1794-1807, 2012). Dr. Kaler pioneered early identification of infants at-risk for Menkes disease using plasma neurochemical measurements and his laboratory utilized a yeast complementation assay to develop a predictive test for responsiveness to copper treatment (N Engl J Med 358:605-614, 2008). Dr. Kaler leads a clinical service for patients with this illness and related disorders of copper metabolism at the NIH Clinical Center. The Kaler laboratory recently rescued a lethal mouse model of Menkes disease by brain-directed adeno-associated virus (AAV)-mediated gene augmentation (Molecular Therapy 19:2114–2123, 2011). Extension of these latter proof-of-concept investigations, in tandem with preclinical toxicology studies, will pave the way for a first-in-human gene therapy trial for Menkes patients with complete loss of function ATP7A genedefects.

Selected Publications

  1. Sharma P, Reichert M, Lu Y, Markello TC, Adams DR, Steinbach PJ, Fuqua BK, Parisi X, Kaler SG, Vulpe CD, Anderson GJ, Gahl WA, Malicdan MCV. Biallelic HEPHL1 variants impair ferroxidase activity and cause an abnormal hair phenotype. PLoS Genet. 2019;15(5):e1008143.

  2. Haddad MR, Choi EY, Zerfas PM, Yi L, Martinelli D, Sullivan P, Goldstein DS, Centeno JA, Brinster LR, Ralle M, Kaler SG. Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev. 2018;10:165-178.

  3. Yi L, Kaler SG. Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration. J Biol Chem. 2018;293(20):7606-7617.

  4. Hu Frisk JM, Kjellén L, Kaler SG, Pejler G, Öhrvik H. Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells. J Immunol. 2017;199(12):4132-4141.

  5. Kaler SG. Microbial peptide de-coppers mitochondria: implications for Wilson disease. J Clin Invest. 2016;126(7):2412-4.

This page was last updated on July 12th, 2017