Two novel mutations in the GAN gene causing giant axonal neuropathy

被引:14
作者
Irad Normendez-Martinez, Monica [1 ]
Monterde-Cruz, Lucero [2 ]
Martinez, Roberto [1 ]
Marquez-Harper, Magdalena [1 ]
Esquitin-Garduno, Nayelli [1 ]
Valdes-Flores, Margarita [2 ]
Casas-Avila, Leonora [2 ]
Ponce de Leon-Suarez, Valeria [2 ]
Javier Romero-Diaz, Viktor [3 ]
Hidalgo-Bravo, Alberto [1 ,2 ]
机构
[1] Med Specialties Hosp, Blvd Milenio 130, Guanajuato 37660, Mexico
[2] Natl Inst Rehabil, Dept Genet, Ave Mexico Xochimilco 289, Mexico City 14389, DF, Mexico
[3] Autonomous Univ State Nuevo Leon, Sch Med, Dept Histol, Monterrey, Mexico
关键词
GAN; Genetics; Giant axonal neuropathy; Incapacity; Neurodegenerative; PROTEIN FAMILIES; GIGAXONIN; DEGRADATION; CYTOSKELETON; SUBFAMILIES; PANTHER; DOMAIN;
D O I
10.1007/s12519-018-0140-z
中图分类号
R72 [儿科学];
学科分类号
100202 ;
摘要
Giant axonal neuropathy (GAN) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. This disorder presents motor and sensitive symptoms with an onset in early childhood. Progressive neurodegeneration makes the patients wheelchair dependent by the end of the second decade of life. Affected individuals do not survive beyond the third decade of life. Molecular analysis has identified mutations in the gene GAN in patients with this disorder. This gene produces a protein called gigaxonin which is presumably involved in protein degradation via the ubiquitin-proteasome system. However, the underlying molecular mechanism is not clearly understood yet. Here we present the first patient from Mexico with clinical data suggesting GAN. Sequencing of the GAN gene was carried out. Changes in the nucleotide sequence were investigated for their possible impact on protein function and structure using the publicly available prediction tools PolyPhen-2 and PANTHER. The patient is a compound heterozygous carrying two novel mutations in the GAN gene. The sequence analysis revealed two missense mutations in the Kelch repeats domain. In one allele, a C > T transition was found in exon 9 at the nucleotide position 55393 (g.55393C > T). In the other allele, a transversion G > T in exon 11 at the nucleotide position 67471 (g.67471G > T) was observed. Both of the bioinformatic tools predicted that these amino acid substitutions would have a negative impact on gigaxonin's function. This work provides useful information for health professionals and expands the spectrum of disease-causing mutations in the GAN gene and it is the first documented case in Mexican population.
引用
收藏
页码:298 / 304
页数:7
相关论文
共 23 条
[1]   A novel mutation in the GAN gene causes an intermediate form of giant axonal neuropathy in an Arab-Israeli family [J].
Abu-Rashid, M. ;
Mahajnah, M. ;
Jaber, L. ;
Kornreich, L. ;
Bar-On, E. ;
Basel-Vanagaite, L. ;
Soffer, D. ;
Koenig, M. ;
Straussberg, R. .
EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY, 2013, 17 (03) :259-264
[2]   A method and server for predicting damaging missense mutations [J].
Adzhubei, Ivan A. ;
Schmidt, Steffen ;
Peshkin, Leonid ;
Ramensky, Vasily E. ;
Gerasimova, Anna ;
Bork, Peer ;
Kondrashov, Alexey S. ;
Sunyaev, Shamil R. .
NATURE METHODS, 2010, 7 (04) :248-249
[3]   Clinicogenetical features of a Japanese patient with giant axonal neuropathy [J].
Akagi, Motohiro ;
Mohri, Ikuko ;
Iwatani, Yoshiko ;
Kagitani-Shimono, Kuriko ;
Okinaga, Takeshi ;
Sakai, Norio ;
Ozono, Keiichi ;
Taniike, Masako .
BRAIN & DEVELOPMENT, 2012, 34 (02) :156-162
[4]   Gigaxonin-controlled degradation of MAP1B light chain is critical to neuronal survival [J].
Allen, E ;
Ding, JQ ;
Wang, W ;
Pramanik, S ;
Chou, J ;
Yau, V ;
Yang, YM .
NATURE, 2005, 438 (7065) :224-228
[5]   GIANT AXONAL NEUROPATHY - UNIQUE CASE WITH SEGMENTAL NEUROFILAMENTOUS MASSES [J].
ASBURY, AK ;
BARINGER, JR ;
BERG, BO ;
GALE, MK ;
COX, SC .
ACTA NEUROPATHOLOGICA, 1972, 20 (03) :237-&
[6]  
BERG BO, 1972, PEDIATRICS, V49, P894
[7]   The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy [J].
Bomont, P ;
Cavalier, L ;
Blondeau, F ;
Hamida, CB ;
Belal, S ;
Tazir, M ;
Demir, E ;
Topaloglu, H ;
Korinthenberg, R ;
Tüysüz, B ;
Landrieu, P ;
Hentati, F ;
Koenig, M .
NATURE GENETICS, 2000, 26 (03) :370-374
[8]   Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport [J].
Ding, JQ ;
Allen, E ;
Wang, W ;
Valle, A ;
Wu, CB ;
Nardine, T ;
Cui, BX ;
Yi, J ;
Taylor, A ;
Jeon, NL ;
Chu, S ;
So, Y ;
Vogel, H ;
Tolwani, R ;
Mobley, W ;
Yang, YM .
HUMAN MOLECULAR GENETICS, 2006, 15 (09) :1451-1463
[9]   Microtubule-associated protein 1B: a neuronal binding partner for gigaxonin [J].
Ding, JQ ;
Liu, JJ ;
Kowal, AS ;
Nardine, T ;
Bhattacharya, P ;
Lee, A ;
Yang, YM .
JOURNAL OF CELL BIOLOGY, 2002, 158 (03) :427-433
[10]   ABNORMALITIES OF THE AXONAL CYTOSKELETON IN GIANT AXONAL NEUROPATHY [J].
DONAGHY, M ;
KING, RHM ;
THOMAS, PK ;
WORKMAN, JM .
JOURNAL OF NEUROCYTOLOGY, 1988, 17 (02) :197-208