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From the Department of Neurology (R.S., L.S.) and Hertie-Institute for Clinical Brain Research (R.S., A.S., L.S.), University of Tübingen; Microarray Facility (M.B.) and Department of Medical Genetics (P.B.), Institute of Human Genetics, Tübingen, Germany; INSERM U679 (A.D., S.F.), Paris; Département de Génétique et Cytogénétique (A.D.), Groupe Hospitalier Pitié-Salpêtrière, Paris; Université Pierre et Marie Curie (S.F.), Paris, France; Department of Neurology (A.D.S.), University of Ulm; Department of Neurology (S.K.), University of Mainz; Department of Behavioural Ecology & Evolutionary Genetics (J.C.M.), Max Planck Institute for Ornithology, Munich, Germany; and Department of Neurology (B.P.v.d.W.), Radboud University Nijmegen Medical Centre, The Netherlands.
Address correspondence and reprint requests to Dr. Ludger Schöls, Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany ludger.schoels{at}uni-tuebingen.de
Objective: Hereditary spastic paraplegias (HSP) are genetically exceedingly heterogeneous. To date, 37 genetic loci for HSP have been described (SPG1-41), among them 16 loci for autosomal dominant disease. Notwithstanding, further genetic heterogeneity is to be expected in HSP, as various HSP families do not link to any of the known HSP loci. In this study, we aimed to map the disease locus in a German family segregating autosomal dominant complicated HSP.
Methods: A genome-wide linkage analysis was performed using the GeneChip Mapping 10Kv2.0 Xba Array containing 10,204 SNP markers. Suggestive loci were further analyzed by mapping of microsatellite markers.
Results: One locus on chromosome 12q23-24, termed SPG36, was confirmed by high density microsatellite fine mapping with a significant LOD score of 3.2. SPG36 is flanked by markers D12S318 and D12S79. Linkage to SPG36 was excluded in >20 additional autosomal dominant HSP families. Candidate genes were selected and sequenced. No disease-causing mutations were identified in the coding regions of ATXN2, HSPB8, IFT81, Myo1H, UBE3B, and VPS29. SPG36 is complicated by a sensory and motor neuropathy; it is therefore the eighth autosomal dominant subtype of complicated HSP.
Conclusion: We report mapping of a new locus for autosomal dominant hereditary spastic paraplegia (HSP) (SPG36) on chromosome 12q23-24 in a German family with autosomal dominant HSP complicated by peripheral neuropathy.
ATR = Achilles tendon reflex; CMAP = compound muscle action potential; CMT = central motor time; DML = distal motor latency; FDI = fist dorsal interosseus muscle; HSP = hereditary spastic paraplegia; MNCV = motor nerve conduction velocity; PTR = patella tendon reflex; SNAP = sensory nerve action potential; SNCV = sensory nerve conduction velocity; SPRS = Spastic Paraplegia Rating Scale; TA = tibialis anterior muscle.
Supplemental data at www.neurology.org
e-Pub ahead of print on April 8, 2009, at www.neurology.org.
Supported by the Deutsche Forschungsgemeinschaft (grant SCHO 754/4-1) and the E-Rare program of the European Union (grant to EUROSPA 01GM0807).
Disclosure: The authors report no disclosures.
Medical Device: GeneChip Mapping 10Kv2.0 Xba Array (Affymetrix, Santa Clara, CA).
Received October 7, 2008. Accepted in final form January 28, 2009.
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