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Novel Mutation in Htra1 in a Family With Diffuse White Matter Lesions and Inflammatory Features Publisher



Ziaei A1, 2, 6, 9 ; Xu X1, 3 ; Dehghani L4 ; Bonnard C5 ; Zellner A1 ; Ng AYJ7 ; Tohari S7 ; Venkatesh B7, 8 ; Haffner C6 ; Reversade B5 ; Shaygannejad V9 ; Pouladi MA1, 2, 10
Authors
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Authors Affiliations
  1. 1. Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), Clinical Neuroscience Institute of Jinan University, 8A Biomedical Grove, Immunos, Level 5, Guangzhou, Guangdong, China
  2. 2. Department of Medicine, National University of Singapore, Clinical Neuroscience Institute of Jinan University, Guangzhou, Guangdong, China
  3. 3. Department of Neurology and Stroke Center, First Affiliated Hospital, Jinan University, Clinical Neuroscience Institute of Jinan University, Guangzhou, Guangdong, China
  4. 4. Department of Tissue Engineering and Regenerative Medicine, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. Institute of Medical Biology (IMB), A*STAR, 8A Biomedical Grove, Immunos, Level 5, Singapore, Singapore
  6. 6. Institute for Stroke and Dementia Research, Klinikum der Universitat Munchen, Ludwig Maximilians University, Munich, Germany
  7. 7. Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, ASTAR, Biopolis, Singapore
  8. 8. Department of Paediatrics, National University of Singapore, Singapore
  9. 9. Department of Neurology, Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Iran
  10. 10. Department of Physiology, National University of Singapore, Singapore

Source: Neurology: Genetics Published:2019


Abstract

Objective To investigate the possible involvement of germline mutations in a neurologic condition involving diffuse white matter lesions. Methods The patients were 3 siblings born to healthy parents. We performed homozygosity mapping, whole-exome sequencing, site-directed mutagenesis, and immunoblotting. Results All 3 patients showed clinical manifestations of ataxia, behavioral and mood changes, premature hair loss, memory loss, and lower back pain. In addition, they presented with inflammatory-like features and recurrent rhinitis. MRI showed abnormal diffuse demyelination lesions in the brain and myelitis in the spinal cord. We identified an insertion in high-temperature requirement A (HTRA1), which showed complete segregation in the pedigree. Functional analysis showed the mutation to affect stability and secretion of truncated protein. Conclusions The patients’ clinical manifestations are consistent with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; OMIM #600142), which is known to be caused by HTRA1 mutations. Because some aspects of the clinical presentation deviate from those reported for CARASIL, our study expands the spectrum of clinical consequences of loss-of-function mutations in HTRA1. Copyright © 2019 The Author(s).