The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease
Abstract
:1. Introduction
2. The AGTPBP1 Gene
2.1. Genomic Structure and Organisation
2.2. Expression Pattern
3. The AGTPBP1 Protein
3.1. Modular Domain Structure
3.2. Expression Pattern
3.3. Role of the AGTPBP1 Protein
4. AGTPBP1 Mutation-Related Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA)
5. The pcd Mouse as an Animal Model for Studying AGTPBP1 Mutation-Related CONDCA
5.1. Degeneration in the Cerebellum
5.1.1. Degeneration of Purkinje Cells
5.1.2. Alterations in Other Neuronal Types in the Cerebella of pcd Mice
5.1.3. Reorganisation of Cerebellar Circuitry in pcd Mice after Purkinje Cell Loss
5.1.4. Alterations in Cerebellar-Dependent Tasks
5.2. Degeneration in the Olfactory Bulb
5.2.1. Degeneration of Mitral Cells
5.2.2. Reorganisation of Synaptic Circuitry after Mitral Cell Loss
5.2.3. Neural Plasticity in the Olfactory Bulb after Mitral Cell Loss
5.2.4. Alterations in Olfactory Task Performance after Mitral Cell Loss
5.3. Degeneration in the Thalamus
5.4. Degeneration in the Retina
5.5. Degeneration of Other Neuronal Types
5.6. Therapeutic Strategies
5.6.1. Stem Cell-Based Transplantation
5.6.2. Preservation of Degenerating Neurons in pcd Mice
5.6.3. Genetically Mediated Therapeutic Approaches
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Patient (Age; Sex; Consanguinity) | Allelic Variant | Consequence | Region Affected | Reference |
---|---|---|---|---|
2-year-old; F; NO | NM_001330701 c.2336-1G>T | Transversion in intron 17. Results in a splice site aberration, a frameshift and premature termination (M780fs) | Cytosolic carboxypeptidase N-terminal domain | [1] |
NM_001330701 c.2736delC | Deletion in exon 21. Results in a frameshift and premature termination (T912Ter) | Zinc-carboxypeptidase domain | [1] | |
12-month-old; M; YES | NM_001330701 c.2752C>T | Transition in exon 21. Results in R918W substitution | Zinc-carboxypeptidase domain | [1] |
7-month-old; M; YES | - | Deletion of exons 1 to 12 | Non-defined | [1] |
Not available | NM_015239.2 c.2632C>T | Cerebellar hypoplasia and lower motor neuron degeneration. Results in R878W substitution | Zinc-carboxypeptidase domain | [4] |
4-year-old; M; NO | NM_001286715 c.2351A>G | Results in a T784C substitution | Non-defined | [2] |
NM_001286715 c.2998C>T | Results in a frameshift and premature termination (R1000Ter) | Zinc-carboxypeptidase domain | ||
15-month-old; M; YES | NM_001286715 c.2342C>T+2T>G | Skips exon 15 (loss of 29 highly conserved aa) | Non-defined modular domain | [2] |
5-year-old; F; NO | NM_001330701 c.2752C>T | Transition in exon 21. Results in R918W substitution | Zinc-carboxypeptidase domain | [1] |
NM_001330701 c.2080T>G | Transversion in exon 15. Results in a Y694D substitution | Non-defined | ||
16-month-old; F; YES | NM_001330701 c.2566C>T | Homozygous transition in exon 19. Results in a Q856 * | Non-defined | [1] |
8-year-old; M; YES | NM_001330701 c.2395C>T | Results in a R799C substitution | Cytosolic carboxypeptidase N-terminal domain | [1] |
8-year-old; M; YES | NM_001330701 c.2566C>T | Results in a P799C substitution | Cytosolic carboxypeptidase N-terminal domain | [1] |
7-month-old; M; YES | NM_001330701 c.2396G>T | Results in a P799L substitution | Cytosolic carboxypeptidase N-terminal domain | [3] |
2-year-old; M; YES | NM_001330701 c.2396G>T | Results in a P799L substitution | Cytosolic carboxypeptidase N-terminal domain | [3] |
20-month-old; F; NO | NM_001330701 c.988C>T | Results in a R330 * | Non-defined | [1] |
Results in a Y912X substitution | Zinc-carboxypeptidase domain | |||
8-year-old; M; YES and 5-year-old; F; YES | NM_001330701 c.2728C>T | Results in a R910C substitution | Zinc-carboxypeptidase domain | [1] |
3 infant sibs; YES | NM_001330701 c.2362C>T | Transition in exon 18. Results in a Q788 * | Cytosolic carboxypeptidase N-terminal domain | [1] |
14-year-old; M; NO | NM_001330701 c.2552C>T | Transition in exon 19, resulting in a T851M substitution | Non-defined | [1] |
NM_001330701 c.2969A>T | transversion in exon 22, resulting in a H990L substitution | Zinc-carboxypeptidase domain | ||
21-month-old; M; YES | NM_001330701 c.3293G>A | Mutation in exon 24, resulting in a S1098N substitution | 3′ end domain | [36] |
17-year-old; F; YES | NM_001330701 c.3293G>A | Mutation in exon 24, resulting in an S1098N substitution | 3′ end domain | [36] |
Feature | Data from [1,2,3,4,36] |
---|---|
Onset | Birth to 20 months |
Gender | 10F, 9M Not available (1) |
Consanguinity | 14/19 Not available (1) |
Progressive degenerative course | 19/20 |
Microcephaly | 11/20 Not available (1) |
Motor delay | 20/20 |
Hypotonia | 19/20 Not available (1) |
Muscle weakness | 16/18 Not available (2) |
Muscle weakness pattern | Tetraparesis/plegia (8) Lower limb (2) Neck (3) Diaphragm/intercostal (4) Not specified (8) |
Muscle atrophy | 9/18 |
Tongue fasciculations | 7/20 Not available (13/20) |
Tendon reflexes | Low or absent (10/20) Normal (3/20) Increased (6/29) Not available (1) |
Ataxia | Yes (6) Not available (12) |
Dystonia | 5/20 Not available (1) |
Spasticity | 7/20 Not available (3/18) |
Respiratory distress | 9/20 Not available (1) |
Feeding difficulties | 13/20 Not available (1) |
Eye movement abnormalities | Detected (12/20) Not detected (6/20) Not available (2/20) |
Hearing | Impaired (1/20) Normal (5/20) Not available (14/20) |
Cognitive delay | 17/20 Not available (3/20) |
Brain MRI | Cerebellar atrophy (18/20) Dysplastic corpus callosum (6/20) Small pons (1/20) Enlarged CSF spaces (1/20) |
Nerve conduction studies | Motor neuropathy (2/20) Axonal motor neuropathy (5/20) Normal (1/18) Not available (12/20) |
Electromyography | Denervation (5/20) Neurogenic (2/20) Normal (1/20) Not available (12/20) |
Allele Name Mutation | Mutation | Clinical Features | Genetic Mutation in AGTPBP1 |
---|---|---|---|
Agtpbp1pcd−1J | Spontaneous | Reduced body size; Ataxia; cerebellar atrophy; postnatal degeneration of thalamic neurons, PCs, MCs and retinal photoreceptors; male infertility; female partial fertility. | Unknown (possibly in regulatory region) |
Agtpbp1pcd−2J | Spontaneous | Hylomorphic allele with reduced | Insertion (~7.8Kb) between exons 14–15 |
Agtpbp1pcd−3J | Spontaneous | Reduced body size; Ataxia; Cerebellar atrophy; postnatal degeneration of thalamic neurons, PCs, MCs and photoreceptors; male infertility; female partial fertility; Reduced number of antral follicles. | Deletion (~12.2 Kb) between intron 5 and exon 8 |
Agtpbp1pcd−4J | ENU-induced mutagenesis | Ataxia; degeneration of PCs | Unknown |
Agtpbp1pcd−5J | Spontaneous | Ataxia; Degeneration of PCs and MCs | Insertion of an aspartic acid residue (D775) in exon 18 |
Agtpbp1pcd−6J | ENU-induced mutagenesis | Ataxia; cerebellar and testicular atrophy; postnatal degeneration of PCs, MCs and photoreceptors; decreased skeletal muscle fiber size; male infertility. | Unknown |
Agtpbp1pcd−7J | Spontaneous | Ataxia; postnatal degeneration of PCs; enlarged hippocampus; abnormal hearing | Unknown |
Agtpbp1pcd−8J | Spontaneous | Affectation of behavior; low size body; Alteration of nervous system development, reproductive, and vision. | Unknown |
Agtpbp1pcd−9J | Spontaneous | Ataxia, but has a slightly later onset than that caused by the original pcd allele. | Unknown |
Agtpbp1pcd-Tg(Dhfr)1jwg | Transgene insertion | Ataxia; degeneration of PCs, MCs and photoreceptor cells; some male infertility, female partial fertility; degeneration of sperm | Random gene disruption |
Agtpbp1Drunk | Mutagenesis | Degeneration of Purkinje cells and photoreceptor cells; Male infertility | Unknown |
Agtpbp1Rio | Mutagenesis | Tremor and abnormal sperm | Unknown |
Agtpbp1babe | ENU-induced mutagenesis | Ataxia; paraparesis | P804 arginine to a termination codon |
Agtpbp1pcd-Btlr | ENU-induced mutagenesis | Ataxia; degeneration of PCs, MCs and photoreceptor cells; male infertility, oligozoospermia and teratozoospermia | a T-to-A transversion in the donor splice site of intron 11 |
Agtpbp1pcd-m2Btlr | ENU-induced mutagenesis | Tremors; decreased body size; reduced activated sperm motility | an A to G transition; destroys the acceptor splice site of intron 7 of the gene |
Agtpbp1pcd-Sid | Spontaneous | Reduced body size; Ataxia; Cerebellar atrophy. | Deletion of exon 7 |
Agtpbp1Gt(IST13517F11)Tigm | Gene trapped allele | one ES cell; unclassified | Chr13:59477801-59478055 bp (-);Chr13:59477801-59477979 bp (-) |
Agtpbp1Gt(OST186151)Lex | Gene trapped allele | Lex-1 (ES Cell) | Chr13:59531904-59544452 bp (-) |
Agtpbp1Gt(OST188387)Lex | Gene trapped allele | Lex-1 (ES Cell) | Chr13:59531902-59533237 bp (-) |
Agtpbp1Gt(OST252171)Lex | Gene trapped allele | Lex-1 (ES Cell) | Chr13:59531904-59544452 bp (-) |
Agtpbp1Gt(OST300426)Lex | Gene trapped allele | Lex-1 (ES Cell) | Chr13:59531904-59544452 bp (-) |
Agtpbp1Gt(OST300428)Lex | Gene trapped allele | Lex-1 (ES Cell) | Chr13:59536248-59536374 bp (-) |
Agtpbp1Gt(OST301743)Lex | Gene trapped allele | Lex-1 (ES Cell) | Chr13:59531913-59536374 bp (-) |
pcdKO | Knock-out | Ataxia; cerebellar atrophy, postnatal degeneration of PCs and photoreceptors. | Deletion of exons 21 and 22 |
Physiopathological Feature | CONDCA Patients | pcd Mice |
---|---|---|
Early-onset | YES | YES |
Progressive degenerative course | YES | YES |
Microcephaly | YES | YES |
Motor delay | YES | YES |
Hypotonia | YES | N.E |
Muscle weakness | YES | YES |
Muscle atrophy | YES | YES |
Tongue fasciculations | Frequent | N.E |
Alteration of tendon reflexes | Frequent | N.E |
Ataxia | Frequent | YES |
Dystonia | Frequent | N.E |
Spasticity | Frequent | N.E |
Respiratory distress | Frequent | N.E |
Feeding difficulties | Frequent | YES |
Eye movement abnormalities | Frequent | N.E |
Defective hearing | Occasional | YES |
Cognitive delay | YES | YES |
Motor and axonal motor neuropathy | Frequent | YES |
Denervation | Frequent | YES |
Olfactory dysfunction | N.E | YES |
Visual deficiency | N.E | YES |
Defective sperm | N.E | YES |
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Baltanás, F.C.; Berciano, M.T.; Santos, E.; Lafarga, M. The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease. Biomedicines 2021, 9, 1157. https://doi.org/10.3390/biomedicines9091157
Baltanás FC, Berciano MT, Santos E, Lafarga M. The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease. Biomedicines. 2021; 9(9):1157. https://doi.org/10.3390/biomedicines9091157
Chicago/Turabian StyleBaltanás, Fernando C., María T. Berciano, Eugenio Santos, and Miguel Lafarga. 2021. "The Childhood-Onset Neurodegeneration with Cerebellar Atrophy (CONDCA) Disease Caused by AGTPBP1 Gene Mutations: The Purkinje Cell Degeneration Mouse as an Animal Model for the Study of this Human Disease" Biomedicines 9, no. 9: 1157. https://doi.org/10.3390/biomedicines9091157