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Kidney International Reports Jun 2021Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis....
INTRODUCTION
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN.
METHODS
We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined.
RESULTS
Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls.
CONCLUSIONS
Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.
PubMed: 34169208
DOI: 10.1016/j.ekir.2021.02.025 -
Scientific Reports Sep 2022Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a...
Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in LILRB1. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases-Graves' disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in LILRB1, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant LILRB1, compared with those with the wild-type LILRB1, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates LILRB1 as a new disease gene for autoimmunity.
Topics: Antigens, CD; Graves Disease; Humans; Leukocyte Immunoglobulin-like Receptor B1; Leukocytes, Mononuclear; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Exome Sequencing
PubMed: 36104364
DOI: 10.1038/s41598-022-19334-x -
Ear and HearingA multisite clinical trial was conducted to obtain cochlear implant (CI) efficacy data in adults with asymmetric hearing loss (AHL) and establish an evidence-based...
OBJECTIVE
A multisite clinical trial was conducted to obtain cochlear implant (CI) efficacy data in adults with asymmetric hearing loss (AHL) and establish an evidence-based framework for clinical decision-making regarding CI candidacy, counseling, and assessment tools. Study hypotheses were threefold: (1) 6-month postimplant performance in the poor ear (PE) with a CI will be significantly better than preimplant performance with a hearing aid (HA), (2) 6-month postimplant performance with a CI and HA (bimodal) will be significantly better than preimplant performance with bilateral HAs (Bil HAs), and (3) 6-month postimplant bimodal performance will be significantly better than aided, better ear (BE) performance.
DESIGN
Forty adults with AHL from four, metropolitan CI centers participated. Hearing criteria for the ear to be implanted included (1) pure-tone average (PTA, 0.5, 1, 2 kHz) of >70 dB HL, (2) aided, monosyllabic word score of ≤30%, (3) duration of severe-to-profound hearing loss of ≥6 months, and (4) onset of hearing loss ≥6 years of age. Hearing criteria for the BE included (1) PTA (0.5, 1, 2, 4 kHz) of 40 to 70 dB HL, (2) currently using a HA, (3) aided, word score of >40%, and (4) stable hearing for the previous 1-year period. Speech perception and localization measures, in quiet and in noise, were administered preimplant and at 3-, 6-, 9-, and 12-months postimplant. Preimplant testing was performed in three listening conditions, PE HA, BE HA, and Bil HAs. Postimplant testing was performed in three conditions, CI, BE HA, and bimodal. Outcome factors included age at implantation and length of deafness (LOD) in the PE.
RESULTS
A hierarchical nonlinear analysis predicted significant improvement in the PE by 3 months postimplant versus preimplant for audibility and speech perception with a plateau in performance at approximately 6 months. The model predicted significant improvement in postimplant, bimodal outcomes versus preimplant outcomes (Bil HAs) for all speech perception measures by 3 months. Both age and LOD were predicted to moderate some CI and bimodal outcomes. In contrast with speech perception, localization in quiet and noise was not predicted to improve by 6 months when comparing Bil HAs (preimplant) to bimodal (postimplant) outcomes. However, when participants' preimplant everyday listening condition (BE HA or Bil HAs) was compared with bimodal performance, the model predicted significant improvement by 3 months for localization in quiet and noise. Lastly, BE HA results were stable over time; a generalized linear model analysis revealed bimodal performance was significantly better than performance with a BE HA at all postimplant intervals for most speech perception measures and localization.
CONCLUSIONS
Results revealed significant CI and bimodal benefit for AHL participants by 3-months postimplant, with a plateau in CI and bimodal performance at approximately 6-months postimplant. Results can be used to inform AHL CI candidates and to monitor postimplant performance. On the basis of this and other AHL research, clinicians should consider a CI for individuals with AHL if the PE has a PTA (0.5, 1, 2 kHz) >70 dB HL and a Consonant-Vowel Nucleus-Consonant word score ≤40%. LOD >10 years should not be a contraindication.
Topics: Adult; Humans; Cochlear Implants; Prospective Studies; Cochlear Implantation; Hearing Loss; Hearing Aids; Speech Perception; Treatment Outcome
PubMed: 37018114
DOI: 10.1097/AUD.0000000000001354 -
Genes Nov 2022High temperature is a major stress in rice production. Although considerable progress has been made in investigating heat tolerance (HT) in rice, the genetic basis of HT...
High temperature is a major stress in rice production. Although considerable progress has been made in investigating heat tolerance (HT) in rice, the genetic basis of HT at the heading stage remains largely unknown. In this study, a novel set of chromosome segment substitution lines (CSSLs) consisting of 113 lines derived from a heat-resistant variety N22 and a heat-sensitive variety 9311 was developed and used for the analysis of the genetic basis of HT. The heat sensitivity index (HSI) calculated based on seed-setting rates under natural and high-temperature environments was used to evaluate the influence of HT at the rice heading stage. In total, five quantitative trait loci (QTLs) associated with HT were detected based on seed-setting rate (SSR) evaluation; these were named , , , and located on chromosomes 6, 7, 8, 9 and 11, respectively. Heat-tolerant alleles of the QTLs were all derived from N22. Among them, overlapped with QTLs identified previously, while the remaining QTLs were found novel. In particular, explained a high phenotypic variation of 26.35% with a LOD score of 10.75, thus deserved to be further validated. These findings will increase our understanding of the genetic mechanism underlying HT and facilitate the breeding of heat-tolerant rice varieties.
Topics: Quantitative Trait Loci; Oryza; Thermotolerance; Phenotype; Plant Breeding; Chromosomes, Plant
PubMed: 36553515
DOI: 10.3390/genes13122248 -
Scientific Reports Jan 2022To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD) in patients with...
To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD) in patients with suspected chronic coronary syndrome (CCS). A total of 706 patients with suspected CCS, referred for Coronary Computed Tomography Angiography, were included. cTn concentrations were measured using the Singulex hs-cTnI (limit of detection [LoD] 0.08 ng/L) and Roche hs-cTnT (LoD 3 ng/L) assays. Obstructive coronary artery disease (CAD) was defined as ≥ 50% coronary stenosis. Cardiovascular risk was determined by the NORRISK2-score. Median age of the patients was 65 (range 28-87) years, 35% were women. All patients had hs-cTnI concentrations above the LoD (median 1.9 [Q1-3 1.2-3.6] ng/L), 72% had hs-cTnT above the LoD (median 5 [Q1-3 2-11] ng/L). There was a graded relationship between hs-cTn concentrations and coronary artery calcium. Only hs-cTnI remained associated with CAD in adjusted analyses (OR 1.20 95% Confidence Interval [1.05-1.38]), p = 0.009). The C-statistics for hs-cTnI and hs-cTnT were 0.65 (95% CI [0.60-0.69]) and 0.60 (0.56-0.64). The highest specificity and negative predictive values for CAD were in the lowest NORRISK2-tertile. hs-cTn concentrations provide diagnostic information in patients with suspected CCS, with superior performance of hs-cTnI compared to hs-cTnT in regard to CAD. The diagnostic performance appeared best in those with low cardiovascular risk.
Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Biomarkers; Computed Tomography Angiography; Coronary Artery Disease; Coronary Vessels; Female; Heart; Humans; Limit of Detection; Male; Middle Aged; Norway; Predictive Value of Tests; Troponin I; Troponin T
PubMed: 35042885
DOI: 10.1038/s41598-022-04850-7 -
European Journal of Human Genetics :... Aug 2019Language is a uniquely human ability, and failure to attain this ability can have a life-long impact on the affected individuals. This is particularly true for...
Language is a uniquely human ability, and failure to attain this ability can have a life-long impact on the affected individuals. This is particularly true for individuals with specific language impairment (SLI), which is defined as an impairment in normal language development in the absence of any other developmental disability. Although SLI displays high heritability, family-based linkage studies have been hampered by an unclear mode of Mendelian segregation, variable disease penetrance, and heterogeneity of diagnostic criteria. We performed genome-wide parametric linkage analysis and homozygosity mapping in 14 consanguineous families from Pakistan segregating SLI. Linkage analysis revealed a multipoint LOD score of 4.18 at chromosome 2q in family PKSLI05 under a recessive mode of inheritance. A second linkage score of 3.85 was observed in family PKSLI12 at a non-overlapping locus on chromosome 2q. Two other suggestive linkage loci were found in family PKSLI05 on 14q and 22q with LOD scores of 2.37 and 2.23, respectively, that were also identified in homozygosity mapping. Reduction to homozygosity was observed on chromosomes 2q, 5p, 8q, 14q, 17q, and 22q. Each homozygosity region occurred in multiple PKSLI families. We report new SLI loci on chromosomes 2 and 8 and confirm suggestive SLI linkage loci on chromosomes 5, 14, 17, and 22 reported previously in the population of Robinson Crusoe Island. These findings indicate that linkage and homozygosity mapping in consanguineous families can improve genetic analyses in SLI and suggest the involvement of additional genes in the causation of this disorder.
Topics: Chromosome Mapping; Consanguinity; Family Health; Female; Genetic Loci; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Lod Score; Male; Pakistan; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Specific Language Disorder
PubMed: 30976110
DOI: 10.1038/s41431-019-0398-1 -
Nature Communications Sep 2021Evolutionary constraints may significantly bias phenotypic change, while "breaking" from such constraints can lead to expanded ecological opportunity. Ray-finned fishes...
Evolutionary constraints may significantly bias phenotypic change, while "breaking" from such constraints can lead to expanded ecological opportunity. Ray-finned fishes have broken functional constraints by developing two jaws (oral-pharyngeal), decoupling prey capture (oral jaw) from processing (pharyngeal jaw). It is hypothesized that the oral and pharyngeal jaws represent independent evolutionary modules and this facilitated diversification in feeding architectures. Here we test this hypothesis in African cichlids. Contrary to our expectation, we find integration between jaws at multiple evolutionary levels. Next, we document integration at the genetic level, and identify a candidate gene, smad7, within a pleiotropic locus for oral and pharyngeal jaw shape that exhibits correlated expression between the two tissues. Collectively, our data show that African cichlid evolutionary success has occurred within the context of a coupled jaw system, an attribute that may be driving adaptive evolution in this iconic group by facilitating rapid shifts between foraging habitats, providing an advantage in a stochastic environment such as the East African Rift-Valley.
Topics: Animals; Biological Evolution; Cichlids; Ecosystem; Feeding Behavior; Female; Jaw; Lod Score; Male; Mouth; Pharynx; Quantitative Trait Loci; Sequence Analysis, DNA; X-Ray Microtomography
PubMed: 34531386
DOI: 10.1038/s41467-021-25755-5 -
NPJ Genomic Medicine Aug 2023Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive...
Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chicken molecular development studies, we demonstrated that this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity. We thus delineate an Ihh enhancer active in mammalian eye development whose variant causes human microphthalmia, anophthalmia and ocular coloboma. The findings highlight disease causation by an intronic variant affecting the expression of a neighboring gene, delineating molecular pathways of eye development.
PubMed: 37580330
DOI: 10.1038/s41525-023-00364-x -
Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene.Movement Disorders : Official Journal... Dec 2020In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney...
BACKGROUND
In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction.
OBJECTIVE
To demonstrate linkage and to identify the underlying genetic cause of disease.
METHODS
Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed.
RESULTS
Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS.
CONCLUSIONS
Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.
Topics: Chorea; Humans; LIM-Homeodomain Proteins; Nail-Patella Syndrome; Skull; Transcription Factors
PubMed: 32949189
DOI: 10.1002/mds.28244 -
Toxins Dec 2022Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory...
INTRODUCTION
Snakebite is an urgent, unmet global medical need causing significant morbidity and mortality worldwide. Varespladib is a potent inhibitor of venom secretory phospholipase A (sPLA) that can be administered orally via its prodrug, varespladib-methyl. Extensive preclinical data support clinical evaluation of varespladib as a treatment for snakebite envenoming (SBE). The protocol reported here was designed to evaluate varespladib-methyl for SBE from any snake species in multiple geographies.
METHODS AND ANALYSIS
BRAVO (Broad-spectrum Rapid Antidote: Varespladib Oral for snakebite) is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study to evaluate the safety, tolerability, and efficacy of oral varespladib-methyl plus standard of care (SoC) vs. SoC plus placebo in patients presenting with acute SBE by any venomous snake species. Male and female patients 5 years of age and older who meet eligibility criteria will be randomly assigned 1:1 to varespladib-methyl or placebo. The primary outcome is the Snakebite Severity Score (SSS) that has been modified for international use. This composite outcome is based on the sum of the pulmonary, cardiovascular, nervous, hematologic, and renal systems components of the updated SSS.
ETHICS AND DISSEMINATION
This protocol was submitted to regulatory authorities in India and the US. A Clinical Trial No Objection Certificate from the India Central Drugs Standard Control Organisation, Drug Controller General-India, and a Notice to Proceed from the US Food and Drug Administration have been obtained. The study protocol was approved by properly constituted, valid institutional review boards or ethics committees at each study site. This study is being conducted in compliance with the April 1996 ICH Guidance for Industry GCP E6, the Integrated Addendum to ICH E6 (R2) of November 2016, and the applicable regulations of the country in which the study is conducted. The trial is registered on Clinical trials.gov, NCT#04996264 and Clinical Trials Registry-India, 2021/07/045079 000062.
Topics: Humans; Male; Female; Snake Bites; Phospholipases A2, Secretory; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase II as Topic
PubMed: 36668842
DOI: 10.3390/toxins15010022