Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation

被引:22
作者
Saveri, Paola [1 ]
De Luca, Maria [2 ]
Nisi, Veronica [2 ]
Pisciotta, Chiara [1 ]
Romano, Roberta [2 ]
Piscosquito, Giuseppe [3 ]
Reilly, Mary M. [4 ]
Polke, James M. [5 ]
Cavallaro, Tiziana [6 ]
Fabrizi, Gian Maria [6 ]
Fossa, Paola [7 ]
Cichero, Elena [7 ]
Lombardi, Raffaella [1 ]
Lauria, Giuseppe [1 ,8 ]
Magri, Stefania [9 ]
Taroni, Franco [9 ]
Pareyson, Davide [1 ]
Bucci, Cecilia [2 ]
机构
[1] Fdn IRCCS Ist Neurol Carlo Besta, Dept Clin Neurosci, I-20133 Milan, Italy
[2] Univ Salento, Dept Biol & Environm Sci & Technol, I-73100 Lecce, Italy
[3] IRCCS ICS Maugeri Spa SB, Funct Neuromotor Rehabil Unit, Sci Inst Telese Terme, I-82037 Telese Terme, Benevento, Italy
[4] UCL Queen Sq Inst Neurol, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England
[5] Natl Hosp Neurol & Neurosurg, Dept Neurogenet, UCL Inst Neurol, London WC1N 3BG, England
[6] Univ Verona, Dept Neurosci Biomed & Movement Sci, I-37134 Verona, Italy
[7] Univ Genoa, Dept Pharm, Sch Med & Pharmaceut Sci, I-16132 Genoa, Italy
[8] Univ Milan, Dept Biomed & Clin Sci Luigi Sacco, I-20157 Milan, Italy
[9] Fdn IRCCS Ist Neurol Carlo Besta, Unit Med Genet & Neurogenet, Dept Diagnost & Technol, I-20133 Milan, Italy
关键词
RAB7A; Charcot-Marie-Tooth disease type 2B; CMT2B; peripheral sensory neuropathy; NGF; RAB7; mutations; axons; lysosomes; autophagy; neurite outgrowth; endocytosis; EGFR; GROWTH-FACTOR RECEPTOR; INTERMEDIATE-FILAMENTS; NERVOUS-SYSTEM; MICE LACKING; DISEASE; NEUROPATHY; TRANSPORT; FAMILY; RILP; TRAFFICKING;
D O I
10.3390/cells9041028
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.
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页数:21
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共 61 条
  • [1] Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus
    Auer-Grumbach, M
    De Jonghe, P
    Wagner, K
    Verhoeven, K
    Hartung, HP
    Timmerman, V
    [J]. NEUROLOGY, 2000, 55 (10) : 1552 - 1557
  • [2] Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci
    Auer-Grumbach, M
    Wagner, K
    Timmerman, V
    De Jonghe, P
    Hartung, HP
    [J]. NEUROLOGY, 2000, 54 (01) : 45 - 52
  • [3] Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations - A review
    Auer-Grumbach, M
    De Jonghe, P
    Verhoeven, K
    Timmerman, V
    Wagner, K
    Hartung, HP
    Nicholson, GA
    [J]. ARCHIVES OF NEUROLOGY, 2003, 60 (03) : 329 - 334
  • [4] Rab7 Mutants Associated with Charcot-Marie-Tooth Disease Cause Delayed Growth Factor Receptor Transport and Altered Endosomal and Nuclear Signaling
    BasuRay, Soumik
    Mukherjee, Sanchita
    Romero, Elsa G.
    Seaman, Matthew N. J.
    Wandinger-Ness, Angela
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (02) : 1135 - 1149
  • [5] Rab7: A key to lysosome biogenesis
    Bucci, C
    Thomsen, P
    Nicoziani, P
    McCarthy, J
    van Deurs, B
    [J]. MOLECULAR BIOLOGY OF THE CELL, 2000, 11 (02) : 467 - 480
  • [6] Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes
    Cantalupo, G
    Alifano, P
    Roberti, V
    Bruni, CB
    Bucci, C
    [J]. EMBO JOURNAL, 2001, 20 (04) : 683 - 693
  • [7] rab7 activity affects epidermal growth factor: Epidermal growth factor receptor degradation by regulating endocytic trafficking from the late endosome
    Ceresa, BP
    Bahr, SJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (02) : 1099 - 1106
  • [8] Charcot-Marie-Tooth type 2B disease-causing RAB7A mutant proteins show altered interaction with the neuronal intermediate filament peripherin
    Cogli, Laura
    Progida, Cinzia
    Thomas, Claire L.
    Spencer-Dene, Bradley
    Donno, Claudia
    Schiavo, Giampietro
    Bucci, Cecilia
    [J]. ACTA NEUROPATHOLOGICA, 2013, 125 (02) : 257 - 272
  • [9] CMT2B-associated Rab7 mutants inhibit neurite outgrowth
    Cogli, Laura
    Progida, Cinzia
    Lecci, Raffaella
    Bramato, Roberta
    Kruettgen, Alex
    Bucci, Cecilia
    [J]. ACTA NEUROPATHOLOGICA, 2010, 120 (04) : 491 - 501
  • [10] Increased activation of the epidermal growth factor receptor in transgenic mice overexpressing epigen causes peripheral neuropathy
    Dahlhoff, Maik
    Emrich, Daniela
    Wolf, Eckhard
    Schneider, Marlon R.
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2013, 1832 (12): : 2068 - 2076