Two novel CYP7B1 mutations in Italian families with SPG5: a clinical and genetic study.
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive weakness and spasticity in the lower limbs. Spasticity may occur in isolation (''pure'' HSP) or may be accompanied by other features. Although autosomal recessive HSPs usually have clinically complex phenotypes, mutations within a few genes underlie pure forms. Recently the gene (CYP7B1) responsible for SPG5, a pure recessive HSP, has been identified. The six CYP7B1 coding exons were analysed in four Italian families. Complete clinical assessment was performed in all patients. Blood CYP7B1 mRNA levels were assessed in three patients and six controls. Brain MRI and (18)F-fluoro-deoxy-glucose positron emission tomography (PET) scan were conducted in three patients. Two novel homozygous mutations were identified. Both result in a frameshift and the introduction of a premature stop codon at the C-terminal of the protein. Patients have reduced blood CYP7B1 mRNA levels, suggesting nonsense mediated RNA decay. Although clinical assessment showed a pure form of spastic paraplegia, MRI demonstrated white matter abnormalities in three patients and PET scan revealed cerebellar hypometabolism in one. Based on the results, we report the first Italian families with SPG5 molecular characterization and describe two novel truncating mutations in CYP7B1. The recessive character, the truncating nature of the mutations, and the reduced peripheral blood CYP7B1 mRNA levels suggest that the development of the disease is associated with a loss of function. SPG5 is considered a pure form of HSP, but MRI and PET findings in our patients suggest that SPG5 phenotype may be broader than the pure presentation.
Criscuolo
Chiara
C
Dipartimento di Scienze Neurologiche, Università degli Studi di Napoli Federico II, Via Pansini 5, Naples 80131, Italy. sky569@libero.it
Filla
Alessandro
A
Coppola
Giovanni
G
Rinaldi
Carlo
C
Carbone
Rosa
R
Pinto
Stefano
S
Wang
Qing
Q
de Leva
Maria Fulvia
MF
Salvatore
Elena
E
Banfi
Sandro
S
Brunetti
Arturo
A
Quarantelli
Mario
M
Geschwind
Daniel H
DH
Pappatà
Sabina
S
De Michele
Giuseppe
G
D000328:Adult; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics; D000072474:Cytochrome P450 Family 7; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013250:Steroid Hydroxylases / Q000235:genetics*
D018389:Codon, Nonsense; D005819:Genetic Markers; D012333:RNA, Messenger; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human