Diagnosis of hereditary spastic paraplegias (hsp) by indentification of a mutation in the kiaa1840 gene or protein

Abstract

The invention relates to an ex vivo method of diagnosing or predicting an hereditary spastic paraplegias (HSP), in a subject, which method comprises detecting a mutation in the KIAA1840 gene or protein (spatacsin), wherein said mutation is indicative of. an hereditary spastic paraplegias (HSP).

1 . An ex vivo method of diagnosing or predicting an hereditary spastic paraplegias (HSP), in a subject, which method comprises detecting a mutation in the KIAA1840 gene or protein (spatacsin), as compared to a control population, wherein said mutation is indicative of a hereditary spastic paraplegia (HSP). 
     
     
         2 . The method according to  claim 1 , which comprises the step consisting of detecting a KIAA1840 mutation in a nucleic acid sample obtained from the subject, as compared to a control population, wherein the presence of a mutation is indicative of a hereditary spastic paraplegia (HSP). 
     
     
         3 . The method according to  claim 1 , wherein said KIAA1840 mutation is selected from the group consisting of:
 the substitutions: c.6100C>T, c.2198T>G, c.118OT 1  c.1235C>G, c.2833A>G, C.1951OT, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, C.2444+1OC, c.2697G>A, C.5470OT, C.5870OG, C.6091OT, c.6477+4 A>G, C.6856OT, c.1282A>T, C.5974OT,   the deletions: c.529-533delATATT, c.6451delG, c.6832 — 6833delAG, c.1203delA, c.1549 — 1550delCT, c.6737 — 6740delTTGA, c.1471 — 1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704 — 705delAT, c.5989 — 5992delCTGT, c.5532 — 5533delCA, c.5769delT, c.6739 — 6742delGAGT, c.4307 — 4308delAA c.733 — 734delAT, and   the insertions: c.7029 — 7030insT, c.2850 — 2851insT, c.3741 — 3742insA, c.5982 — 5983insCTCT, c.5986 — 5987insT, c.3075 — 3076insA c.2842 — 2843insG.   
     
     
         4 . The method according to  claim 1 , which comprises the step consisting of detecting a mutation in the KIAA1840 protein or detecting a truncated form of the KIAA1840 protein contained in a sample obtained from the subject, as compared to a control population, wherein the presence of a mutation in the KIAA1840 protein or a truncated form of the KIAA1840 protein is indicative of a hereditary spastic paraplegia (HSP). 
     
     
         5 . The method according to  claim 4 , wherein a monoclonal or polyclonal antibody recognizing the wild-type KIAA1840 protein is used to detect the presence of the wild-type protein or one of its truncated forms. 
     
     
         6 . The method according to  claim 4 , wherein the truncated KIAA1840 protein is selected from the group consisting of SEQ ID NO:149 to SEQ ID NO:164 and SEQ ID NO:166 to SEQ ID NO:188. 
     
     
         7 . An isolated nucleic acid specifically hybridizable to a region of KIAA1840 gene sequence that contains a mutation selected from the group consisting of
 the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, C.5870OG, C.6091OT, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT,   the deletions: c.529-533delATATT, c.6451delG, c.6832 — 6833delAG, c.1203delA, c.1549 — 1550delCT, c.6737 — 6740delTTGA, c.1471 — 1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704 — 705delAT, c.5989 — 5992delCTGT, c.5532 — 5533delCA, c.5769delT, c.6739 — 6742delGAGT, c.4307 — 4308delAA c.733 1     —   734delAT, and   the insertions: c.7029 — 7030insT, c.2850 — 2851insT, c.3741 — 3742insA, c.5982 — 5983insCTCT, c.5986 — 5987insT, c.3075 — 3076insA c.2842 — 2843insG.   
     
     
         8 . An isolated nucleic acid specifically hybridizable to a region consisting of 10 nucleotides upstream and 10 nucleotides downstream of a mutation selected from the group consisting of
 the substitutions: c.6100C>T, c.2198T>G, C.118OT, C.1235OG, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, C.5870OG, c.6091C>T, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT,   the deletions: c.529-533delATATT, c.6451delG, c.6832 — 6833delAG, c.1203delA, c.1549 — 1550delCT, c.6737 — 6740delTTGA, c.1471 — 1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704 — 705delAT, c.5989 — 5992delCTGT, c.5532 — 5533delCA, c.5769delT, c.6739 — 6742delGAGT, c.4307 — 4308delAA c.733 — 734delAT, and   the insertions: c.7029 — 7030insT, c.2850 — 2851insT, c.3741 — 3742insA, c.5982 — 5983insCTCT, c.5986 — 5987insT, c.3075 — 3076insA c.2842 — 2843insG, of the KIAA1840 gene sequence.   
     
     
         9 . An isolated nucleic acid complementary to a region of KIAA1840 gene sequence that contains a mutation selected from the group consisting of:
 the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, C.1951OT, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, c.5870C>G, C.6091OT, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT,   the deletions: c.529-533delATATT, c.6451delG, c.6832 — 6833delAG, c.1203delA, c.1549 — 1550delCT, c.6737 — 6740delTTGA, c.1471 — 1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704 — 705delAT, c.5989 — 5992delCTGT, c.5532 — 5533delCA, c.5769delT, c.6739 — 6742delGAGT, c.4307 — 4308delAA c.733 — 734delAT, and   the insertions: c.7029 — 7030insT, c.2850 — 2851insT, c.3741 — 3742insA, c.5982 — 5983insCTCT, c.5986 — 5987insT, c.3075 — 3076insA c.2842 — 2843insG.   
     
     
         10 . Isolated nucleic acid according to  claim 9 , consisting of at least 20 nucleotides. 
     
     
         11 . The use of an isolated nucleic acid according to any of  claims 7  to  10  as a primer or probe. 
     
     
         12 . An isolated nucleic acid, which comprises or consists in a KIAA1840 gene sequence that contains one or several mutation(s) selected from the group consisting of
 the substitutions: c.6100C>T, c.2198T>G, c.118OT 1  c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 OG, c.2316+1 G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, c.5870C>G, C.6091 OT, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT,   the deletions: c.529-533delATATT, c.6451delG, c.6832 — 6833delAG, c.1203delA, c.1549 — 1550delCT, c.6737 — 6740delTTGA, c.1471 — 1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704 — 705delAT, c.5989 — 5992delCTGT, c.5532 — 5533delCA, c.5769delT, c.6739 — 6742delGAGT, c.4307 — 4308delAA c.733 — 734delAT, and   the insertions: c.7029 — 7030insT, c.2850 — 2851insT, c.3741 — 3742insA, c.5982 — 5983insCTCT, c.5986 — 5987insT, c.3075 — 3076insA c.2842 — 2843insG or a sequence complementary thereto.   
     
     
         13 . An isolated polypeptide which comprises the amino acid sequence of KIAA1840 containing one or several mutation(s) selected from the group consisting of p.Q40X, p.H77_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401 KfsX415, p.S412X, p.K428X, p.L491 DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, P.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, P.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997 — 1998delfsX2056, p.R2031X, p.R2034X, p.A2151 PfsX2172, p.12246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349. 
     
     
         14 . An isolated monoclonal or polyclonal antibody that specifically recognizes a KIAA1840 protein containing a mutation selected from the group consisting of p.Q40X, p.H77_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401 KfsX415, p.S412X, p.K428X, p.L491 DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, P.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, P.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997 — 1998delfsX2056, p.R2031X, p.R2034X, p.A2151PfsX2172, p.12246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.