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Distal Hereditary Motor Neuropathy in Korean Patients with a Small Heat Shock Protein 27 Mutation

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Distal Hereditary Motor Neuropathy in Korean Patients with a Small Heat Shock Protein 27 Mutation EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 40, No. 3, 304-312, June 2008 DOI 10.3858/emm.2008.40.3.304 Distal hereditary motor neuropathy in Korean patients with a small heat shock protein 27 mutation Ki Wha Chung1*, Sang-Beom Kim2*, ing analysis revealed that fatty infiltrations tended to Sun Young Cho3, Su Jin Hwang3, progressively extend distal to proximal muscles in low- Sun Wha Park1, Sung Hee Kang1, er extremities. In addition, fatty infiltrations in thigh Joonki Kim1, Jeong Hyun Yoo4 muscles progressed to affect posterior and anterior compartments but to lesser extents in medial compart- and Byung-Ok Choi3,5 ment, which differs from CMT1A patients presenting with severe involvements of posterior and medial com- 1Department of Biological Science partments but less involvement of anterior compart- Kongju National University ment. The authors describe the clinical and neuro- Gongju 314-701, Korea 2 imaging findings of the first Korean dHMN patients with Department of Neurology Kyung Hee University the HSP27 Ser135Phe mutation. To our knowledge, East-West Neo Medical Center this is the first report of the neuroimaging findings of Seoul 134-727, Korea dHMN type II. 3Department of Neurology 4Department of Radiology Keywords: Asian continental ancestry group; Charcot- Ewha Medical Research Center Marie-Tooth disease; heat-shock proteins; magnetic Ewha Womans University, School of Medicine resonance imaging; spinal muscular atrophies of Seoul 158-710, Korea childhood 5Corresponding author: Tel, 82-2-2650-2842; Fax, 82-2-2650-2652; E-mail, [email protected] *These authors contributed equally to this work. Introduction Distal hereditary motor neuropathies (dHMNs) are Accepted 7 March 2008 pure motor peripheral neuropathies, but are other- Abbreviations: CMT, Charcot-Marie-Tooth disease; dHMN, distal wise a clinically and genetically heterogeneous hereditary motor neuropathy; FDS, functional disability scale; group of disorders characterized by weakness and HSP27, heat shock protein 27; MRI, magnetic resonance imaging; wasting of the distal muscles of both upper and NCV, nerve conduction velocity lower limbs (Irobi et al., 2006). Distal HMN closely resembles Charcot-Marie-Tooth disease type 2 (CMT2), apart from the absence of the sensory abnormalities, and is difficult to distinguish from Abstract CMT2, because sensory signs are often lacking in CMT2 patients (Evgrafov et al., 2004; Tang et al., Distal hereditary motor neuropathy (dHMN) is a hetero- 2005). Therefore, clinical and electrophysiological geneous disorder characterized by degeneration of examinations are essential to confirm a diagnosis motor nerves in the absence of sensory abnormalities. of dHMN, or CMT2. Recently, mutations in the small heat shock protein 27 Mutations in the gene encoding the 27 kDa (HSP27) gene were found to cause dHMN type II or small heat shock protein 27 (HSP27, also called Charcot-Marie-Tooth disease type 2F (CMT2F). The au- heat shock 27-kD protein 1, HSPB1) have been thors studied 151 Korean axonal CMT or dHMN fami- shown to be causal in Charcot-Marie-Tooth di- sease type 2F (CMT2F; OMIM 606595) and dHMN lies, and found a large Korean dHMN type II family with type II (OMIM 608634). Since mutations of the the Ser135Phe mutation in HSP27. This mutation was HSP27 gene were first identified in an English inherited in an autosomal dominant manner, and was family with dHMN type II and in Russian family with well associated with familial members with the dHMN CMT2F in 2004, six missense mutations (Arg- phenotype. This mutation site is located in the 127Trp, Arg136Trp, Ser135Phe, Thr151Ile, Pro- α-crystallin domain and is highly conserved between 182Ser and Pro182Leu) have been discovered in different species. The frequency of this HSP27 muta- families with dHMN or CMT2F (Evgrafov et al., tion in Koreans was 0.6%. Magnetic resonance imag- 2004; Kijima et al., 2005; Tang et al., 2005). The dHMN with HSP27 mutation 305 majority of HSP27 mutations have been found in thus, in the present study, we tried to identify fatty dHMN patients in the α-crystallin domain, excep- infiltrations compatible with length-dependent axonal ting Pro182Ser and Pro182Leu, which are in the degeneration and sequential muscle involvement C-terminal extension (Evgrafov et al., 2004; Kijima in family members. et al., 2005). The α-crystallin domain is a highly In this study, we identified a missense mutation, conserved region within the small HSP superfamily HSP27 Ser135Phe in 12 members of a large and mutations in this motif can cause loss of HSP Korean family with dHMN type II, and described chaperone activity (Muchowski et al., 1999). the characteristics of clinical and MRI findings of The HSP27 gene is located on chromosome affected members. 7q11.23 and belongs to the superfamily of small stress induced proteins, and HSP27 protein shows sequence similarity with mammalian α-crystallin Materials and Methods proteins (Plumier et al., 1997). The expression of HSP27 is induced in response to various environ- Subjects mental challenges and developmental transitions We enrolled 151 unrelated Korean axonal CMT or (Lee et al., 2005; Arya et al., 2007). As a molecular dHMN families. In the FC197 dHMN family which chaperone, HSP27 protein protects cells from encompassed six generations, 15 individuals from stress, blocks apoptosis signals, and is involved in three generations (IV to VI) were patients, and 12 cell motility and cytoskeletal stabilization (Wagstaff of these underwent molecular and clinical exami- et al., 1999; Hirano et al., 2004; Heo et al., 2006; nations. Six patients in the upper three generations Williams et al., 2006; Arrigo et al., 2007). In addi- (I to III) were assumed to have dHMN by history tion, the overexpression of HSP27 has been asso- (Figure 1). Paternity and maternity in the FC197 ciated with various neurodegenerative diseases, family confirmed by genotyping 15 STR markers such as Alzheimer’s disease (Shimura et al., 2004), using a human identification kit (Applied Biosystems, Parkinson disease (Renkawek et al., 1999), Alexan- Foster City, CA). In addition, 200 healthy controls der disease (Head et al., 1993), and amyotrophic were recruited from our Department of Neurology. lateral sclerosis (Vleminckx et al., 2002). All participants included in this study provided Magnetic resonance imaging (MRI) is useful for written informed consent according to the protocol evaluating skeletal muscle physiopathologies (May approved by the Ethics Committee of Ewha et al., 2000; Farber and Buckwalter, 2002), and Womans University Hospital (Seoul, Korea). Figure 1. Pedigree of the HSP27 Ser135Phe mutation in the dHMN family. The open symbols represent unaffected members (□, ○) and filled symbols affected members (■, ●). Half-filled symbol ( ◘ ) indicates an unaffected individual harboring the Ser135Phe mutation. Asterisks (*) indicate that a DNA sample was available. 306 Exp. Mol. Med. Vol. 40(3), 304-312, 2008 Mutation screening ulnar, peroneal, tibial, and sural nerves were deter Genomic DNA was extracted from whole blood mined in 12 patients. Recordings were obtained using QIAamp DNA blood kits (Qiagen, Hilden, using standard methods with surface stimulation Germany). The 17p11.2-p12 duplication or deletion and recording electrodes. Motor conduction velo- was first examined for all involved FC197 familial cities (MCVs) of the median and ulnar nerves were members (affected: 12; unaffected: 11). Then muta- determined by stimulating at the elbow or wrist, tions in HSP27 and in Cx32, EGR2, MPZ, NEFL, while recording compound muscle action potentials PMP22, MFN2, DNM2, HSP22 and BSCL2 were (CMAPs) over the abductor pollicis brevis and screened by direct DNA sequencing of all exons abductor digiti quinti, respectively. In the same way, and flanking intronic regions. PCR was carried out the MCVs of peroneal and tibial nerves were in a total volume of 30 μl containing 50 ng of determined by stimulating at the knee and ankle, genomic DNA, 0.5 pmol of each primer, 200 μmol while recording CMAPs over the extensor digitorum brevis and abductor hallucis, respectively. CMAP of each dNTP, 2 mmol of MgCl2, 0.6 U of Taq DNA polymerase and 1X buffer (Promega, Madison, amplitudes were measured from baseline to ne- WI), using an GeneAmp PCR system 9700 (Applied gative peak values. Sensory conduction velocities Biosystems). PCR consisted of pre-denaturation (SCVs) were obtained over a finger-wrist segment (94oC for 5 min), 35 amplification cycles (94oC for from the median and ulnar nerves by orthodromic 40 s, 56oC for 30 s, and 72oC for 90 s), and a final scoring, and were also recorded for sural nerves. extension (72oC for 7 min). The primer sequences Sensory nerve action potential (SNAP) amplitudes and PCR conditions used are available on request were measured from positive peaks to negative from the corresponding author. PCR products were peaks. purified using EXOSAP-IT kits (USB Co.), and analyzed using an ABI 3100 automatic se- MRI study quencing analyzer (Applied Biosystems). In order to detect sequence variations, we used the Seq- MRI was performed on 12 dHMN patients in a Scape (Ver. 2.1) program (Applied Biosystems), supine position using a 1.5-T system (Siemens and confirmed the presence of mutations by Vision; Siemens, Erlangen, Germany). Leg muscle analyzing both DNA strands. imaging was carried out in axial [field of view (FOV) 24-32 cm, slice thickness 10 mm, and slice gap 0.5-1.0 mm] and coronal planes (FOV 38-40 Clinical assessment cm, slice thickness 4-5 mm, slice gap 0.5-1.0 mm). The following protocol was used in all patients: Clinical information was obtained in a standardized T1-weighted spin-echo (SE) (TR/TE 570-650/14-20, manner, and included assessments of motor and 512 matrixes), T2-weighted SE (TR/TE 2800- sensory impairments, deep tendon reflexes, and 4000/96-99, 512 matrixes), and fat-suppressed muscle atrophy. Muscle strengths of flexor and T2-weighted SE (TR/TE 3090-4900/85-99, 512 extensor muscles were assessed manually using matrixes) in both planes.
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