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Cystic fibrosis in Chilean patients: Analysis of 36 common CFTR gene mutations
(2011)
Guillermo Lay-Son
;
Alonso Puga
;
Pedro Astudillo
;
REPETTO LISBOA, MARIA GABRIELA
Scopus© Citations 20 1
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Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network
(2023-12-01)
Lopez-Campos, José Luis
;
Rapun, Noelia
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CZISCHKE LJUBETIC, KAREN NICOLE
;
Jardim, José R.
;
Acquier, Mariano Fernandez
Background: Knowledge of the frequency of rare SERPINA1 mutations could help in the management of alpha1 antitrypsin deficiency (AATD). The present study aims to assess the frequencies of rare and null alleles and their respiratory and hepatic pathogenicity. Methods: This is a secondary analysis of a study that evaluated the viability of the Progenika diagnostic genotyping system in six different countries by analyzing 30,827 samples from cases of suspected AATD. Allele-specific genotyping was carried out with the Progenika A1AT Genotyping Test which analyses 14 mutations in buccal swabs or dried blood spots samples. SERPINA1 gene sequencing was performed for serum AAT-genotype discrepancies or by request of the clinician. Only cases with rare mutations were included in this analysis. Results: There were 818 cases (2.6%) carrying a rare allele, excluding newly identified mutations. All were heterozygous except for 20 that were homozygous. The most frequent alleles were the M-like alleles, PI*Mmalton and PI*Mheerlen. Of the 14 mutations included in the Progenika panel, there were no cases detected of PI*Siiyama, PI*Q0granite falls and PI*Q0west. Other alleles not included in the 14-mutation panel and identified by gene sequencing included PI*Mwürzburg, PI*Zbristol, and PI*Zwrexham, and the null alleles PI*Q0porto, PI*Q0madrid, PI*Q0brescia, and PI*Q0kayseri. Conclusions: The Progenika diagnostic network has allowed the identification of several rare alleles, some unexpected and not included in the initial diagnostic panel. This establishes a new perspective on the distribution of these alleles in different countries. These findings may help prioritize allele selection for routine testing and highlights the need for further research into their pathogenetic role.
Scopus© Citations 5 1
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Major Histocompatibility Complex Class I-Related Chain A (MICA) Allelic Variants Associate With Susceptibility and Prognosis of Gastric Cancer
(2021)
Karen Toledo-Stuardo
;
Carolina H. Ribeiro
;
Andrea Canals
;
Marcela Morales
;
Valentina Gárate
<jats:p>Gastric cancer (GC) is the fifth most prevalent type of cancer worldwide. Gastric tumor cells express MICA protein, a ligand to NKG2D receptor that triggers natural killer (NK) cells effector functions for early tumor elimination. <jats:italic>MICA</jats:italic> gene is highly polymorphic, thus originating alleles that encode protein variants with a controversial role in cancer. The main goal of this work was to study <jats:italic>MICA</jats:italic> gene polymorphisms and their relationship with the susceptibility and prognosis of GC. Fifty patients with GC and 50 healthy volunteers were included in this study. MICA alleles were identified using Sanger sequencing methods. The analysis of <jats:italic>MICA</jats:italic> gene sequence revealed 13 MICA sequences and 5 MICA-short tandem repeats (STR) alleles in the studied cohorts We identified MICA<jats:sup>*</jats:sup>002 (<jats:sup>*</jats:sup>A9) as the most frequent allele in both, patients and controls, followed by MICA<jats:sup>*</jats:sup>008 allele (<jats:sup>*</jats:sup>A5.1). MICA<jats:sup>*</jats:sup>009/049 allele was significantly associated with increased risk of GC (OR: 5.11 [95% CI: 1.39–18.74], <jats:italic>p</jats:italic> = 0.014). The analysis of MICA-STR alleles revealed a higher frequency of MICA<jats:sup>*</jats:sup>A5 in healthy individuals than GC patients (OR = 0.34 [95% CI: 0.12–0.98], <jats:italic>p</jats:italic> = 0.046). Survival analysis after gastrectomy showed that patients with MICA<jats:sup>*</jats:sup>002/002 or MICA<jats:sup>*</jats:sup>002/004 alleles had significantly higher survival rates than those patients bearing MICA<jats:sup>*</jats:sup>002/008 (<jats:italic>p</jats:italic> = 0.014) or MICA<jats:sup>*</jats:sup>002/009 (MICA<jats:sup>*</jats:sup>002/049) alleles (<jats:italic>p</jats:italic> = 0.040). The presence of threonine in the position MICA-181 (MICA<jats:sup>*</jats:sup>009/049 allele) was more frequent in GC patients than controls (<jats:italic>p</jats:italic> = 0.023). Molecular analysis of MICA-181 showed that the presence of threonine provides greater mobility to the protein than arginine in the same position (MICA<jats:sup>*</jats:sup>004), which could explain, at least in part, some immune evasion mechanisms developed by the tumor. In conclusion, our findings suggest that the study of MICA alleles is crucial to search for new therapeutic approaches and may be useful for the evaluation of risk and prognosis of GC and personalized therapy.</jats:p>
Scopus© Citations 12 1
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Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis
(2022)
José Luis Lopez-Campos
;
Lourdes Osaba
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CZISCHKE LJUBETIC, KAREN NICOLE
;
José R. Jardim
;
Mariano Fernandez Acquier
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Introduction</jats:title> <jats:p>Currently, strategies for improving alpha1 antitrypsin deficiency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey. </jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specific genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the mutations were found or one variant was detected in heterozygous status and the AAT serum level was < 60 mg/dl, or if requested by the clinician in charge.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>The study included 30,827 samples: 30,458 (94.7%) with final results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The prevalence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identified. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our results confirm the viability of this diagnostic system for genotyping AATD conducted simultaneously in different countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.</jats:p> </jats:sec>
Scopus© Citations 9 1
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Analysing an allelic series of rare missense variants of <i>CACNA1I</i> in a Swedish schizophrenia cohort
(2021)
David Baez-Nieto
;
Andrew Allen
;
Seth Akers-Campbell
;
Lingling Yang
;
Nikita Budnik
<jats:title>Abstract</jats:title> <jats:p>CACNA1I is implicated in the susceptibility to schizophrenia by large-scale genetic association studies of single nucleotide polymorphisms. However, the channelopathy of CACNA1I in schizophrenia is unknown. CACNA1I encodes CaV3.3, a neuronal voltage-gated calcium channel that underlies a subtype of T-type current that is important for neuronal excitability in the thalamic reticular nucleus and other regions of the brain. Here, we present an extensive functional characterization of 57 naturally occurring rare and common missense variants of CACNA1I derived from a Swedish schizophrenia cohort of more than 10 000 individuals. Our analysis of this allelic series of coding CACNA1I variants revealed that reduced CaV3.3 channel current density was the dominant phenotype associated with rare CACNA1I coding alleles derived from control subjects, whereas rare CACNA1I alleles from schizophrenia patients encoded CaV3.3 channels with altered responses to voltages. CACNA1I variants associated with altered current density primarily impact the ionic channel pore and those associated with altered responses to voltage impact the voltage-sensing domain. CaV3.3 variants associated with altered voltage dependence of the CaV3.3 channel and those associated with peak current density deficits were significantly segregated across affected and unaffected groups (Fisher’s exact test, P = 0.034). Our results, together with recent data from the SCHEMA (Schizophrenia Exome Sequencing Meta-Analysis) cohort, suggest that reduced CaV3.3 function may protect against schizophrenia risk in rare cases. We subsequently modelled the effect of the biophysical properties of CaV3.3 channel variants on thalamic reticular nucleus excitability and found that compared with common variants, ultrarare CaV3.3-coding variants derived from control subjects significantly decreased thalamic reticular nucleus excitability (P = 0.011). When all rare variants were analysed, there was a non-significant trend between variants that reduced thalamic reticular nucleus excitability and variants that either had no effect or increased thalamic reticular nucleus excitability across disease status. Taken together, the results of our functional analysis of an allelic series of &gt;50 CACNA1I variants in a schizophrenia cohort reveal that loss of function of CaV3.3 is a molecular phenotype associated with reduced disease risk burden, and our approach may serve as a template strategy for channelopathies in polygenic disorders.</jats:p>
Scopus© Citations 22 1

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