Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria

Background Cell survival critically depends on the integrity of mitochondria, which play a pivotal role during apoptosis. Extensive mitochondrial damage promotes release of pro-apoptotic factors from the intermembrane space of mitochondria. Released mitochondrial proteins include Smac/DIABLO and HTRA2/Omi, which inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of apoptosis proteins. Aims Here we investigated the cause of extreme hypertonia at birth, alternating with hypotonia, with the subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, intractable seizures and early death in four patients from two unrelated families. The patients showed lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, evolving brain atrophy and disturbed cristae structure in muscle mitochondria. Methods and results Using whole-exome sequencing, we identified missplicing mutation and a 5 bp deletion in HTRA2, encoding HTRA2/Omi. This protein was completely absent from the patients' fibroblasts, whose growth was impaired and which were hypersensitive to apoptosis. Expression of HtrA2/Omi or of the proteolytically inactive HTRA2/Omi protein restored the cells' apoptotic resistance. However, cell growth was only restored by the proteolytically active protein. Conclusions This is the first report of recessive deleterious mutations in HTRA2 in human. The clinical phenotype, the increased apoptotic susceptibility and the impaired cell growth recapitulate those observed in the Htra2 knockout mice and in mutant mice with proteolytically inactive HTRA2/Omi. Together, they underscore the importance of both chaperone and proteolytic activities of HTRA2/Omi for balanced apoptosis sensitivity and for brain development. Absence of HTRA2/Omi is associated with severe neurodegenerative disorder of infancy, abnormal mitochondria, 3-methylglutaconic aciduria and increased sensitivity to apoptosis.

[1]  S. Johansson,et al.  HTRA2 p.G399S in Parkinson disease, essential tremor, and tremulous cervical dystonia , 2015, Proceedings of the National Academy of Sciences.

[2]  Xinran Liu,et al.  Neural-Specific Deletion of Htra2 Causes Cerebellar Neurodegeneration and Defective Processing of Mitochondrial OPA1 , 2014, PloS one.

[3]  T. Walsh,et al.  Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease , 2014, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Wan,et al.  Upregulation of mitochondrial protease HtrA2/Omi contributes to manganese-induced neuronal apoptosis in rat brain striatum , 2014, Neuroscience.

[5]  E. Rugarli,et al.  The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission , 2014, The Journal of cell biology.

[6]  Sungwook Han,et al.  HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA. , 2013, Biochimica et biophysica acta.

[7]  E. Alnemri,et al.  Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging , 2012, Cell Death and Differentiation.

[8]  M. Durán,et al.  Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature , 2013, Journal of Inherited Metabolic Disease.

[9]  A. M. van der Bliek,et al.  Mitochondrial Fission, Fusion, and Stress , 2012, Science.

[10]  J. Schuurs-Hoeijmakers,et al.  Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness , 2012, Nature Genetics.

[11]  E. Rugarli,et al.  Mitochondrial quality control: a matter of life and death for neurons , 2012, The EMBO journal.

[12]  Wei Li,et al.  Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. , 2011, American journal of human genetics.

[13]  A. Singleton,et al.  Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. , 2008, Human molecular genetics.

[14]  P. Vandenabeele,et al.  The mitochondrial serine protease HtrA2/Omi: an overview , 2008, Cell Death and Differentiation.

[15]  Sebastian Brandner,et al.  Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice , 2004, Molecular and Cellular Biology.

[16]  S. Srinivasula,et al.  Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice , 2003, Nature.

[17]  C. Southan,et al.  The HtrA family of proteases: implications for protein composition and cell fate. , 2002, Molecular cell.

[18]  Emad S. Alnemri,et al.  Structural insights into the pro-apoptotic function of mitochondrial serine protease HtrA2/Omi , 2002, Nature Structural Biology.

[19]  M. Maurizi.  Love it or cleave it: Tough choices in protein quality control , 2002, Nature Structural Biology.

[20]  M. Meisler,et al.  Progressive Loss of Striatal Neurons Causes Motor Dysfunction in MND2 Mutant Mice and Is Not Prevented by Bcl-2 , 2002, Experimental Neurology.

[21]  S. Lowe,et al.  Generation and Characterization of Smac/DIABLO-Deficient Mice , 2002, Molecular and Cellular Biology.

[22]  H. Nakayama,et al.  A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. , 2001, Molecular cell.

[23]  Robert L Moritz,et al.  Identification of DIABLO, a Mammalian Protein that Promotes Apoptosis by Binding to and Antagonizing IAP Proteins , 2000, Cell.

[24]  J C Reed,et al.  IAP family proteins--suppressors of apoptosis. , 1999, Genes & development.

[25]  Y. Lazebnik,et al.  Caspases: enemies within. , 1998, Science.