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Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia
- Source :
- The American journal of human genetics 107(2), 364-373 (2020). doi:10.1016/j.ajhg.2020.06.015, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2020, 107 (2), pp.364-373. ⟨10.1016/j.ajhg.2020.06.015⟩, Am J Hum Genet, Am. J. Hum. Genet. 107, 364-373 (2020)
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
Abstract
- International audience; We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.
- Subjects :
- 0301 basic medicine
Male
mitochondrial metabolism
Neurological disorder
Mitochondrion
0302 clinical medicine
Spastic
Child
Genetics (clinical)
Exome sequencing
ComputingMilieux_MISCELLANEOUS
Brain Diseases
genetics [Brain Diseases]
Neurodegenerative Diseases
encephalopathy
Mitochondria
3. Good health
Pedigree
developmental delay
Phenotype
Female
genetics [Mitochondrial Proteins]
movement disorder
medicine.symptom
Adult
Adolescent
Hereditary spastic paraplegia
Encephalopathy
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Developmental Delay
Exome Sequencing
Hereditary Spastic Paraplegia
Hpdl
Leigh-like Syndrome
Mitochondrial Metabolism
Movement Disorder
Mitochondrial Proteins
Leigh-like syndrome
03 medical and health sciences
Young Adult
Report
ddc:570
genetics [Spastic Paraplegia, Hereditary]
Genetics
medicine
Humans
Spasticity
Amino Acid Sequence
hereditary spastic paraplegia
Allele
Alleles
Spastic Paraplegia, Hereditary
business.industry
HPDL
medicine.disease
030104 developmental biology
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
genetics [Neurodegenerative Diseases]
Immunology
genetics [Mitochondria]
business
exome sequencing
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 00029297 and 15376605
- Database :
- OpenAIRE
- Journal :
- The American journal of human genetics 107(2), 364-373 (2020). doi:10.1016/j.ajhg.2020.06.015, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2020, 107 (2), pp.364-373. ⟨10.1016/j.ajhg.2020.06.015⟩, Am J Hum Genet, Am. J. Hum. Genet. 107, 364-373 (2020)
- Accession number :
- edsair.doi.dedup.....03a6b1699a506f1613e8922c058bf730