title: Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations.
abstract: We set up a new denaturing high-performance liquid chromatography (DHPLC)-based protocol to screen patients with autosomal dominant hereditary spastic paraplegia (AD-HSP) for mutations in SPG4. Six patients had a complicated form and 49 a pure HSP phenotype. We also analyzed 19 unrelated patients presenting with an HSP phenotype (pure in 17 and complicated in two subjects) but no clear family history, as such patients may be cases of dominant inheritance with low penetrance. The overall frequency of SPG4 mutations in our study of HSP (in which prior linkage data were unavailable) was 32.4%, rising to 46.9% when only pure AD-HSP patients were considered. This figure falls well within the range reported in different populations. Rather as expected, the clinical data available for the patients did not support an easy genotype-phenotype correlation. Moreover, the clinical picture was not influenced by the length of the predicted residual gene product. As well as identifying novel variants in SPG4, this study constitutes the molecular characterization of the largest cohort of Italian AD-HSP patients studied to date. In addition, it provided an efficient, cost-effective, and reliable detection protocol for mutational screening of SPG4, which might facilitate medical genetic counseling.
authors.affiliation: Molecular Medicine, IRCCS - Bambino Gesù, Rome, Italy.
authors.forename: Clarice
authors.initials: C
authors.lastname: Patrono
authors.forename: Valentina
authors.initials: V
authors.lastname: Scarano
authors.forename: Federica
authors.initials: F
authors.lastname: Cricchi
authors.forename: Mariarosa A B
authors.initials: MA
authors.lastname: Melone
authors.forename: Maria
authors.initials: M
authors.lastname: Chiriaco
authors.forename: Alessandro
authors.initials: A
authors.lastname: Napolitano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Malandrini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: De Michele
authors.forename: Lucia
authors.initials: L
authors.lastname: Petrozzi
authors.forename: Carlo
authors.initials: C
authors.lastname: Giraldi
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.forename: Serena
authors.initials: S
authors.lastname: Servidei
authors.forename: Carlo
authors.initials: C
authors.lastname: Casali
authors.forename: Alessandro
authors.initials: A
authors.lastname: Filla
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D016368:Frameshift Mutation; D005799:Genes, Dominant; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D016415:Sequence Alignment; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human