Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate.

Abstract

OBJECTIVE:

We aimed to decipher the molecular genetic basis of disease in a cohort of children with a uniform clinical presentation of neonatal irritability, spastic or dystonic quadriplegia, virtually absent psychomotor development, axonal neuropathy, and elevated blood/CSF lactate.

METHODS:

We performed whole-exome sequencing of blood DNA from the index patients. Detected compound heterozygous mutations were confirmed by Sanger sequencing. Structural predictions and a bacterial activity assay were performed to evaluate the functional consequences of the mutations. Mass spectrometry, Western blotting, and protein oxidation detection were used to analyze the effects of selenoprotein deficiency.

RESULTS:

Neuropathology indicated laminar necrosis and severe loss of myelin, with neuron loss and astrogliosis. In 3 families, we identified a missense (p.Thr325Ser) and a nonsense (p.Tyr429*) mutation in SEPSECS, encoding the O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, which was previously associated with progressive cerebellocerebral atrophy. We show that the mutations do not completely abolish the activity of SEPSECS, but lead to decreased selenoprotein levels, with demonstrated increase in oxidative protein damage in the patient brain.

CONCLUSIONS:

These results extend the phenotypes caused by defective selenocysteine biosynthesis, and suggest SEPSECS as a candidate gene for progressive encephalopathies with lactate elevation.

• Authors: Anna-Kaisa Anttonen, Taru Hilander, Tarja Linnankivi, Pirjo Isohanni, Rachel L French, Yuchen Liu, Miljan Simonović, Dieter Söll, Mirja Somer, Dorota Muth-Pawlak, Garry L Corthals, Anni Laari, Emil Ylikallio, Marja Lähde, Leena Valanne, Tuula Lönnqvist, Helena Pihko, Anders Paetau, Anna-Elina Lehesjoki, Anu Suomalainen, Henna Tyynismaa
• Journal: Neurology (Neurology) Vol. 85 Issue 4 Pg. 306-15 (Jul 28 2015) ISSN: 1526-632X [Electronic] United States
• PMID: 26115735 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Academy of Neurology.

Chemical References

• Selenoproteins
• Lactic Acid
• Amino Acyl-tRNA Synthetases
• O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, human

Topics

• Adolescent
• Amino Acyl-tRNA Synthetases (genetics)
• Brain (metabolism, pathology)
• Brain Diseases, Metabolic, Inborn (blood, cerebrospinal fluid, genetics, metabolism)
• Child
• Child, Preschool
• Female
• Humans
• Lactic Acid (blood, cerebrospinal fluid)
• Male
• Mutation
• Oxidative Stress (genetics)
• Selenoproteins (biosynthesis, deficiency)