Diagnosis of hereditary spastic paraplegias (hsp) by identification of a mutation in the zfyve26 gene or protein

Abstract

The Invention relates to an ex vivo method of diagnosing or predicting a hereditary spastic paraplegias (HSP), in a subject, which method comprises detecting a mutation in the ZFYVE26 gene or protein (spastizin), wherein said mutation is indicative of a hereditary spastic paraplegias (HSP).

1 . An ex vivo method of diagnosing or predicting a hereditary spastic, paraplegias (HSP) in a subject, which method comprises detecting a mutation in the ZFYVE26 gene or protein (spastizin) in a sample obtained from said subject, wherein said mutation is indicative of a hereditary spastic paraplegias (HSP). 
     
     
         2 . The method according to  claim 1 , wherein said method comprises the steps consisting of detecting a ZFYVE26 mutation in a nucleic acid sample obtained from the subject wherein the presence of a mutation is indicative of a hereditary spastic paraplegia (HSP). 
     
     
         3 . The method according to  claim 1 , wherein said ZFYVE26 mutation is:
 a substitution selected from the group consisting of c.307G>T, c.427G>T, c.1240G>T, c.1477C>T, c.2182C>T, c.4312C>T, c.5422C>T, c.5791−6G>A/r.5791 — 5792ins5791-4 — 5791-1, c.5485−1G>A, c.7128+2T>A/r.6987 — 7128del, and c.6011G>C,   a deletion selected from the group c.2049delT, c.4068 — 4069delTG, c.5036delT, c.6702 — 6771del,   an insertion selected from the group consisting of c.2331 — 2332insA, c.6296 — 6297insT,   a complex rearrangement which is g.67316025 — 67319414del/g.67316025 — 67316026insTCTA/g.67319319 — 673194 14inv.   
     
     
         4 . The method according to  claim 1 , which comprises the steps consisting of detecting a mutation in the ZFYVE26 protein (spastizin) or detecting a truncated form of the ZFYVE26 protein contained in a sample obtained from the subject, wherein the presence of a mutation in the ZFYVE26 protein or a truncated form of the ZFYVE26 protein is indicative of a hereditary spastic paraplegias (HSP). 
     
     
         5 . The method according to  claim 4 , wherein in step (b) a monoclonal or polyclonal antibody recognizing the wild-type ZFYVE26 protein is used to detect the presence of the wild-type protein one of its truncated forms. 
     
     
         6 . The method according to  claim 4 , wherein in step (b) the truncated ZFYVE26 protein is selected from the group consisting of SEQ ID NO: 105 to SEQ ID NO:117. 
     
     
         7 . An isolated nucleic acid specifically hybridizable a region of ZFYVE26 gene sequence that contains a mutation which is:
 a substitution selected from the group consisting of c.427G>T, c.1240G>T, c.1477C>T, c.2182C>T, c.4312C>T, c.5422C>T, c.5791−6G>A, c.5485−1G>A, c.7128+2T>A, and c.6011G>C,   a deletion selected from the group consisting of c.2049delT, c.4068 — 4069delTG, c.5036delT, c.6702 — 6771del,   an insertion selected from the group consisting of c.2331 — 2332insA, or c.6296 — 6297insT   a complex rearrangement which is g.67316025 — 67319414del/g.67316025 — 67316026insTCTA/g.67319319 — 673194 14inv.   
     
     
         8 . The use of an isolated nucleic acid according to  claim 7  for the detection of a mutation in the ZFYVE26 gene sequence. 
     
     
         9 . The use of an isolated nucleic acid according to  claim 7  as a primer or probe. 
     
     
         10 . An isolated nucleic acid, which comprises or consists in a ZFYVE26 gene sequence that contains one or several mutation(s) selected from the group consisting of:
 the substitutions: c.427G>T, c.1240G>T, c.1477C>T, c.2182C>T, c.4312C>T, c.5422C>T, c.5791−6G>A, c.5485−1G>A, c.7128+2T>A, c.6011G>C,   the deletions: c.2049delT, c.4068 — 4069delTG, c.5036delT, c.6702 — 6771del,   the insertions: c.2331 — 2332insA, c.6296 — 6297insT,   the complex rearrangements: g.67316025 — 67319414del/g.67316025 — 67316026insTCTA/g.67319319 — 673194 14inv.   
     
     
         11 . An isolated polypeptide which comprises the amino acid sequence of ZFYVE26 containing one or several mutation(s) selected from the group consisting of p.E103X, p.E143X, p.E414X, p.Q493X, p.F683LfsX685, p.R728X, p.D778RfsX15793, p.R1209fsX1220, p.C1356fsX1356, p.R1438X, p.L1679RfsX1687, p.Q1808X, p.A1931PfxX1957X, p.S2004T, p.L2099LfsX2111, p.W2234CfsX2238, p.R2329RfsX2337. 
     
     
         12 . An isolated monoclonal or polyclonal antibody that specifically recognizes a ZFYVE26 protein containing a mutation selected from the group consisting of p.E103X, p.E143X, p.E414X, p.Q493X, p.F683LfsX685, p.R728X, p.D778RfsX793, p.R1209fsX1220, p.C1356fsX1356, p.R1438X, p.L1679RfsX1687, p.Q1808X, p.A1931PfxX1957X, p.S2004T, p.L2099LfsX2111, p.W2234CfsX2238, p.R2329RfsX2337. 
     
     
         13 . The isolated nucleic acid of  claim 7  further comprising at least a second mutation which is a c.307G>T substitution. 
     
     
         14 . The isolated nucleic acid of  claim 10  further comprising at least a second mutation which is a c.307G>T substitution. 
     
     
         15 . The method according to  claim 2 , wherein said ZFYVE26 mutation is:
 a substitution selected from the group consisting of c.307G>T, c.427G>T, c.1240G>T, c.1477C>T, c.2182C>T, c.4312C>T, c.5422C>T, c.5791−6G>A/r.5791 — 5792ins5791-4 — 5791-1, c.5485−1G>A, c.7128+2T>A/r.6987 — 7128del, and c.6011G>C,   a deletion selected from the group c.2049delT, c.4068 — 4069delTG, c.5036delT, c.6702 — 6771del,   an insertion selected from the group consisting of c.2331 — 2332insA, c.6296 — 6297insT,   a complex rearrangement which is g.67316025 — 67319414del/g.67316025 — 67316026insTCTA/g.67319319 — 673194 14inv.