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Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by cerebellar ataxia and retinopathy. SCA7 is caused by a CAG expansion in the ATXN7 gene, which results in an extended polyglutamine (polyQ) tract in the encoded protein, the ataxin-7. PolyQ expanded ataxin-7 elicits neurodegeneration in cerebellar Purkinje cells, however, its impact on the SCA7-associated retinopathy remains to be addressed. Since Müller glial cells play an essential role in retinal homeostasis, we generate an inducible model for SCA7, based on the glial Müller MIO-M1 cell line. The SCA7 pathogenesis has been explained by a protein gain-of-function mechanism, however, the contribution of the mutant RNA to the disease cannot be excluded. In this direction, we found nuclear and cytoplasmic foci containing mutant RNA accompanied by subtle alternative splicing defects in MIO-M1 cells. RNA foci were also observed in cells from different lineages, including peripheral mononuclear leukocytes derived from SCA7 patient, suggesting that this molecular mark could be used as a blood biomarker for SCA7. Collectively, our data showed that our glial cell model exhibits the molecular features of SCA7, which makes it a suitable model to study the RNA toxicity mechanisms, as well as to explore therapeutic strategies aiming to alleviate glial dysfunction. [ABSTRACT FROM AUTHOR]

Background: Autosomal recessive congenital ichthyoses (ARCI) are inherited disorders produced by mutations in essential genes for the skin function. A low prevalence of this disease has been resported worldwide; however, in a recent study, we identified a large cluster of ARCI families who resided in the High Mountains Region from the Veracruz State, Mexico. Thus, we aimed to identify the causative mutation of ARCI and describe the high prevalence of this disease in this region. Methods: We selected seven familiar trios and performed whole‐exome sequencing to identify the mutation associated with ARCI. To validate the identified mutation, we performed Sanger sequencing in 62 patients, 30 unaffected relatives, and 100 healthy volunteers. Finally, we performed molecular modeling to investigate the possible functional consequences produced by the mutation. Results: We identified a novel homozygous mutation (c.1054C>G [p.Pro352Ala]) in the exon 7 of the TGM1 gene in all the patients. We calculated a prevalence rate of ARCI of 74:100,000 (1:1,348) in the studied communities. Molecular modeling revealed that the mutation leads to a nonconservative amino acid substitution, which is very probably damaging to the protein structure/function. Conclusions: We report a novel mutation in the TGM1 gene in 62 Mexican patients. The unusually high frequency of this mutation suggests a founder effect; however, further haplotype analysis is necessary to corroborate this hypothesis. In this respect, to our knowledge, the prevalence of ARCI found in the studied communities is the highest observed worldwide. [ABSTRACT FROM AUTHOR]

Extensive damage to nigrostriatal dopaminergic neurons leads to Parkinson's disease (PD). To date, the most effective treatment has been administration of levodopa (L-DOPA) to increase dopaminergic tone. This treatment leads to responses that vary widely among patients, from predominantly beneficial effects to the induction of disabling, abnormal movements (L-DOPA induced dyskinesia (LID)). Similarly, experimental studies have shown animals with widely different degrees of LID severity. In this study, unilateral injections of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB) produced more than 90% depletion of dopamine in both the striatum and the substantia nigra reticulata (SNr) of rats. Population analysis showed that dopamine depletion levels were clustered in a single population. In contrast, analysis of abnormal involuntary movements (AIMs) induced by L-DOPA treatment of 6-OHDA-lesioned animals yielded two populations: one with mild LID, and the other with severe LID, which are also related to different therapeutic responses. We examined whether the severity of LID correlated with changes in dopamine 3 receptor (D3R) signaling because of the following: (a) D3R expression and the induction of LID are strongly correlated; and (b) dopaminergic denervation induces a qualitative change in D3R signaling in the SNr. We found that the effects of D3R activation on cAMP accumulation and depolarization-induced [3H]-gamma-aminobutyric acid ([3H]-GABA) release were switched. L-DOPA treatment normalized the denervation-induced changes in animals with mild LID. The D3R activation caused depression of both dopamine 1 receptor (D1R)-induced increases in cAMP production and depolarization-induced [3H]-GABA release, which were reversed to their pre-denervation state. In animals with severe LID, none of the denervation-induced changes were reversed. The finding that in the absence of identifiable differences in 6-OHDA and L-DOPA treatment, two populations of animals with different D3R signaling and LIDs severity implies that mechanisms intrinsic to the treated subject determine the segregation. [ABSTRACT FROM AUTHOR]

Introduction: Charcot-Marie-Tooth disease (CMT) is a neuropathy that affects sensory and motor nerves. The most common CMT subtype is CMT1A due to a PMP22 duplication of a 1.5 Mb fragment on the 17p11.2-p12. The development of a specific molecular technique that detects the PMP22 duplication is necessary for the diagnosis of CMT1A., Aim: To establish a routinary test for detection of the PMP22 gene duplication in Mexican population and to estimate the CMT1A frequency in patients clinically diagnosed as CMT., Patients and Methods: A cohort of 157 individuals clinically diagnosed as CMT were analyzed. The detection of the PMP22 gene duplication was performed using the comparative 2-ΔΔCT qPCR method., Results: The comparative 2-ΔΔCT method was sensitive and reliable for the detection of the PMP22 duplication. In order to validate the testing, data was compared with FISH results. Duplication of PMP22 was detected in 79 patients (50.3%). Although CMT1A frequency is different among populations, in Mexican patients it was similar with other populations such as United States, Australia, Finland, Sweden and Spain., Conclusions: The qPCR technique is an accurate and inexpensive method for the diagnosis of CMT1A. This method can be routinely used in Mexico where CMT1A represents ≍ 50% of CMT cases. Molecular diagnosis of CMT1A is essential for the genetic counseling and treatment of patients.

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting 1/8000 individuals. DM1 is a dominant disorder characterized by multisystemic clinical features affecting skeletal muscle, heart and the nervous and endocrine systems. DM1 is caused by an expansion of CTG trinucleotide repeats within the 3'-untranslated region (3'-UTR) of the DMPK gene. This repeat is polymorphic in normal individuals with alleles ranging from 5 to 37 in length. Repeats exceeding a threshold of approximately 50 and reaching up to a number of 4,000 result in disease. This review offers a detailed description of the scientific findings that have allowed the establishment of the molecular basis of the DM1 in the muscle and nervous systems. Currently, it is known that mutant DM1 transcript accumulates in the nucleus of muscle and neuronal cells sequestering nuclear proteins, such as splicing regulators and transcription factors to form nuclear foci that are observed under inmunofluorescence techniques. This event disturbs the expression of several muscular and neuronal genes impairing cell differentiation, which may explain the multiple symptoms of the disease. Finally, the main findings towards the development of a gene therapy for DM1 are discussed.

Background: Charcot-Marie-Tooth (CMT) is the most common inherited disorder of the human peripheral nerve. The mos tfrequent subtype, CMT1A, is associated with duplication of approximately 1.5 Mb fragment in 17p11-p12, that includes the PMP22 gene., Objective: The aim of this study was to describe different strategies used for clinical and molecular CNT1A diagnoses among patients attending the National Rehabilitation Institute of Mexico (INR)., Material and Methods: 17 patients had clinical and electrophysiological features compatible with CMT1. A molecular study using capillary electrophoresis (CE) was performed and a PMP22 gene duplication was detected, Results: Clinical, biochemical and electrophysiological studies constituted the inclusion criteria to establish a CMT1 diagnosis. With CE the duplication of the PMP22 gene was observable and we established a possible CMT1A diagnosis in seven patients. All duplications detected by capillary electrophoresis were corroborated using FISH., Conclusion: CE is a feasible and reliable method to detect PMP22 gene duplication. Using different clinical, electrophysiological and molecular strategies in this patient population allowed us to establish an accurate diagnosis and offer suitable genetic counseling.