Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia

Background and Purpose Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively. Methods Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes. Results Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected. Conclusions We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.

[1]  J. Finsterer,et al.  Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance , 2012, Journal of the Neurological Sciences.

[2]  J. Zaremba,et al.  Screening for the hereditary spastic paraplaegias SPG4 and SPG3A with the multiplex ligation-dependent probe amplification technique in a large population of affected individuals , 2013, Neurological Sciences.

[3]  A. Durr,et al.  REEP1 mutations in SPG31: Frequency, mutational spectrum, and potential association with mitochondrial morpho‐functional dysfunction , 2011, Human mutation.

[4]  M. Pericak-Vance,et al.  Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia , 2011, Clinical genetics.

[5]  C. Blackstone,et al.  Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. , 2011, American journal of human genetics.

[6]  G. Cioni,et al.  Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia , 2011, European journal of neurology.

[7]  H. Yoo,et al.  Autosomal Dominant Hereditary Spastic Paraplegia Relavant with a Novel Thr369Pro Mutation in SPAST Gene , 2011 .

[8]  C. Ki,et al.  Clinical and genetic analysis of a Korean family with hereditary spastic paraplegia type 3. , 2010, Annals of clinical and laboratory science.

[9]  H. J. Schelhaas,et al.  Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[10]  Jae-Sung Lim,et al.  A novel splicing mutation (c.870+3A>G) in SPG4 in a Korean family with hereditary spastic paraplegia , 2010, Journal of the Neurological Sciences.

[11]  M. Mancuso,et al.  Mutation analysis of the SPG4 gene in Italian patients with pure and complicated forms of spastic paraplegia , 2010, Journal of the Neurological Sciences.

[12]  K. Xia,et al.  Receptor expression-enhancing protein 1 gene (SPG31) mutations are rare in Chinese Han patients with hereditary spastic paraplegia. , 2009, Chinese medical journal.

[13]  Christos Proukakis,et al.  Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms , 2008, The Lancet Neurology.

[14]  M. Pericak-Vance,et al.  REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. , 2008, Brain : a journal of neurology.

[15]  A. Durr,et al.  Hereditary spastic paraplegias: an update , 2007, Current opinion in neurology.

[16]  M. Mattingsdal,et al.  Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia , 2007, European journal of neurology.

[17]  O. Witte,et al.  High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia , 2006, Neurology.

[18]  M. Ruberg,et al.  Exon deletions of SPG4 are a frequent cause of hereditary spastic paraplegia , 2006, Journal of Medical Genetics.

[19]  M. Pericak-Vance,et al.  Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. , 2006, American journal of human genetics.

[20]  N. Bresolin,et al.  Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. , 2006, Archives of neurology.

[21]  A. Durr,et al.  Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases , 2005, Journal of Medical Genetics.

[22]  Hee-Jin Kim,et al.  Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia. , 2005, Archives of neurology.

[23]  L. Santoro,et al.  Autosomal dominant hereditary spastic paraplegia: DHPLC‐based mutation analysis of SPG4 reveals eleven novel mutations , 2005, Human mutation.

[24]  K. Xia,et al.  Three novel mutations of the spastin gene in Chinese patients with hereditary spastic paraplegia. , 2004, Archives of neurology.

[25]  L. Schöls,et al.  Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia , 2002, Human mutation.

[26]  K. Tashiro,et al.  Spastin gene mutation in Japanese with hereditary spastic paraplegia , 2002, Journal of medical genetics.

[27]  G. Rouleau,et al.  Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. , 2002, Archives of neurology.

[28]  P. Hedera,et al.  Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia , 2001, Nature Genetics.

[29]  M Hutchinson,et al.  Phenotype of AD-HSP due to mutations in the SPAST gene , 2000, Neurology.

[30]  K. D. White,et al.  Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis , 2000, Journal of medical genetics.

[31]  J. Weissenbach,et al.  Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. , 2000, Human molecular genetics.

[32]  Bertrand Fontaine,et al.  Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia , 1999, Nature Genetics.

[33]  G. Rouleau,et al.  Hereditary spastic paraplegia , 2006, Current neurology and neuroscience reports.

[34]  A. Harding.  CLASSIFICATION OF THE HEREDITARY ATAXIAS AND PARAPLEGIAS , 1983, The Lancet.

[35]  Pask Ea,et al.  HOMOSEXUALITY AS A CRIME. , 1965 .