A novel frameshift mutation of DDHD1 in a Japanese patient with autosomal recessive spastic paraplegia
- 1 August 2016
- journal article
- case report
- Published by Elsevier BV in European Journal of Medical Genetics
- Vol. 59 (8), 413-416
- https://doi.org/10.1016/j.ejmg.2016.05.010
Abstract
Spastic paraplegia (SPG) type 28 is an autosomal recessive SPG caused by mutations in the DDHD1 gene. We examined a Japanese 54-years-old male patient with autosomal recessive SPG. His parents were consanguineous. He needed a wheelchair for transfer due to spastic paraplegia. There was a history of operations for bilateral hallux valgus, thoracic ossification of the yellow ligament, bilateral carpal tunnel syndrome, bilateral ankle contracture, and lumbar spinal canal stenosis. He noticed gait disturbance at age 14. He used a cane for walking in his 40s. On neurological examination, he showed hyperreflexia, spasticity, and weakness in the lower extremities and bilateral Babinski reflexes. Urinary dysfunctions and impaired vibration sense in the lower limbs were observed. By exome sequencing analysis using Agilent SureSelect and Illumina MiSeq, we identified 17,248 homozygous nucleotide variants in the patient. Through the examination of 48 candidate genes known to be responsible for autosomal recessive SPG, we identified a novel homozygous 4-bp deletion, c.914_917delGTAA, p.Ser305Ilefs*2 in exon2 of the DDHD1 gene encoding phosphatidic acid-preferring phospholipase A1 (PA-PLA1). The mutation is expected to cause a frameshift generating a premature stop codon 3-bp downstream from the deletion. In consequence, the DDHD domain that is known to be critical for PLA1 activity is completely depleted in the mutated DDHD1 protein, predicted to be a functionally null mutation of the DDHD1 gene. By Sanger sequencing, we confirmed that both parents are heterozygous for the mutation. This variation was not detected in 474 Japanese control subjects as well as the data of the 1,000G Project. We conclude that the novel mutation in DDHD1 is the causative variant for the SPG28 patient that is the first record of the disease in Japanese population.Keywords
Funding Information
- Duke University
- Medical Institute of Bioregulation
- Kyushu University
- JSPS KAKANHI (26460411)
This publication has 11 references indexed in Scilit:
- Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanismsExperimental Neurology, 2014
- Nonsense-mediated decay in genetic disease: Friend or foe?Mutation Research, 2014
- Phosphatidic Acid (PA)-preferring Phospholipase A1 Regulates Mitochondrial DynamicsPublished by Elsevier BV ,2014
- A Hereditary Spastic Paraplegia Mouse Model Supports a Role of ZFYVE26/SPASTIZIN for the Endolysosomal SystemPLoS Genetics, 2013
- The actions and metabolism of lysophosphatidylinositol, an endogenous agonist for GPR55Prostaglandins & Other Lipid Mediators, 2013
- Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanismsActa Neuropathologica, 2013
- Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic ParaplegiaAmerican Journal of Human Genetics, 2012
- Roles of SAM and DDHD domains in mammalian intracellular phospholipase A1 KIAA0725pBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2012
- Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28)Annals of Neurology, 2005
- Cloning of a Phosphatidic Acid-preferring Phospholipase A1 from Bovine TestisPublished by Elsevier BV ,1998