title: Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family.
abstract: Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan. shiroh46@med.kurume-u.ac.jp
authors.forename: Shiroh
authors.initials: S
authors.lastname: Miura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shibata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Noda
authors.forename: Takayuki
authors.initials: T
authors.lastname: Toyama
authors.forename: Naoka
authors.initials: N
authors.lastname: Iwasaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwaki
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Ayabe
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Aizawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Taniwaki
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fukumaki
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D019457:Chromosome Breakage; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D055724:Electrophysiological Phenomena; D005091:Exons; D005260:Female; D006801:Humans; D007438:Introns; D007564:Japan; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000503:physiopathology; D000074181:Spastin
chemical_list: D017931:DNA Primers; C545250:DYDC1 protein, human; D008565:Membrane Proteins; D004247:DNA; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human