HGG AdvancesPub Date : 2025-01-09Epub Date: 2024-09-30DOI: 10.1016/j.xhgg.2024.100357
Nathaniel K Mullin, Laura R Bohrer, Kristin R Anfinson, Jeaneen L Andorf, Robert F Mullins, Budd A Tucker, Edwin M Stone
{"title":"Exonic splice variant discovery using in vitro models of inherited retinal disease.","authors":"Nathaniel K Mullin, Laura R Bohrer, Kristin R Anfinson, Jeaneen L Andorf, Robert F Mullins, Budd A Tucker, Edwin M Stone","doi":"10.1016/j.xhgg.2024.100357","DOIUrl":"10.1016/j.xhgg.2024.100357","url":null,"abstract":"<p><p>Correct identification of the molecular consequences of pathogenic genetic variants is essential to the development of allele-specific therapies. However, such molecular effects may remain ambiguous following genetic sequence analysis alone. Here, we identify exonic codon-altering variants that are also predicted to disrupt normal RNA splicing in the context of inherited retinal disease. NR2E3 c.932G>A (p.Arg311Gln) is a variant commonly associated with enhanced S cone syndrome. Previous studies using mutagenized cDNA constructs have shown that the arginine to glutamine substitution at position 311 of NR2E3 does not meaningfully diminish function of the rod-specific transcription factor. Using retinal organoids, we explored the molecular consequences of NR2E3 c.932G>A when expressed endogenously during human rod photoreceptor cell development. Retinal organoids carrying the NR2E3 c.932G>A allele expressed a transcript containing a 186-nucleotide deletion of exon 6 within the ligand binding domain. This short transcript was not detected in control organoids or control human donor retina samples. A minigene containing exons 5 and 6 of NR2E3 showed sufficiency of the c.932G>A variant to cause the observed splicing defect. These results support the hypothesis that the pathogenic NR2E3 c.932G>A variant leads to photoreceptor disease by causing a splice defect and not through an amino acid substitution as previously supposed. They also explain the relatively mild effect of Arg311Gln on NR2E3 function in vitro. We also used in silico prediction tools to show that similar changes are likely to affect other inherited retinal disease variants in genes such as CEP290, ABCA4, and BEST1.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100357"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2025-01-09Epub Date: 2024-10-28DOI: 10.1016/j.xhgg.2024.100375
Marcos Chiñas, Daniela Fernandez-Salinas, Vitor R C Aguiar, Victor E Nieto-Caballero, Micah Lefton, Peter A Nigrovic, Joerg Ermann, Maria Gutierrez-Arcelus
{"title":"Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis.","authors":"Marcos Chiñas, Daniela Fernandez-Salinas, Vitor R C Aguiar, Victor E Nieto-Caballero, Micah Lefton, Peter A Nigrovic, Joerg Ermann, Maria Gutierrez-Arcelus","doi":"10.1016/j.xhgg.2024.100375","DOIUrl":"10.1016/j.xhgg.2024.100375","url":null,"abstract":"<p><p>Multiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. In this study, we aimed to identify the key cell types mediating the genetic risk in AS using an unbiased functional genomics approach. We integrated genome-wide association study (GWAS) data with epigenomic and transcriptomic datasets of human immune cells. To quantify enrichment of cell type-specific open chromatin or gene expression in AS risk loci, we used three published methods-LDSC-SEG, SNPsea, and scDRS-that have successfully identified relevant cell types in other diseases. Natural killer (NK) cell-specific open chromatin regions are significantly enriched in heritability for AS, compared to other immune cell types such as T cells, B cells, and monocytes. This finding was consistent between two AS GWAS. Using RNA sequencing data, we validated that genes in AS risk loci are enriched in NK cell-specific gene expression. Using the human Space-Time Gut Cell Atlas, we also found significant upregulation of AS-associated genes predominantly in NK cells. We performed co-localization analyses between GWAS risk loci and genetic variants associated with gene expression (eQTL) to find putative target genes. This revealed four AS risk loci affecting regulation of candidate target genes in NK cells: two known loci, ERAP1 and TNFRSF1A, and two understudied loci, ENTR1 (SDCCAG3) and B3GNT2. Our findings suggest that NK cells may play a crucial role in AS development and highlight four putative target genes for functional follow-up in NK cells.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100375"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2025-01-09Epub Date: 2024-10-31DOI: 10.1016/j.xhgg.2024.100377
Kejia Zhang, Katharina Löhner, Henny H Lemmink, Maartje Boon, Jenna M Lentini, Naduni de Silva, Dragony Fu
{"title":"Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification.","authors":"Kejia Zhang, Katharina Löhner, Henny H Lemmink, Maartje Boon, Jenna M Lentini, Naduni de Silva, Dragony Fu","doi":"10.1016/j.xhgg.2024.100377","DOIUrl":"10.1016/j.xhgg.2024.100377","url":null,"abstract":"<p><p>Epileptic encephalopathies are severe epilepsy syndromes characterized by early onset and progressive cerebral dysfunction. A nonsense variant in the DALR anticodon binding domain containing 3 (DALRD3) gene has been implicated in epileptic encephalopathy, but no other disease-associated variants in DALRD3 have been described. In human cells, the DALRD3 protein forms a complex with the METTL2 methyltransferase to generate the 3-methylcytosine (m3C) modification in specific arginine tRNAs. Here, we identify an individual with a homozygous missense variant in DALRD3 who displays developmental delay, cognitive deficiencies, and multifocal epilepsy. The missense variant substitutes an arginine residue to cysteine (R517C) within the DALR domain of the DALRD3 protein that is required for binding tRNAs. Cells derived from the individual homozygous for the DALRD3-R517C variant exhibit reduced levels of m3C modification in arginine tRNAs, indicating that the R517C variant impairs DALRD3 function. Notably, the DALRD3-R517C protein displays reduced association with METTL2 and loss of interaction with substrate tRNAs. Our results uncover another loss-of-function variant in DALRD3 linked to epileptic encephalopathy disorders. Importantly, these findings underscore DALRD3-dependent tRNA modification as a key contributor to proper brain development and function.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100377"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2025-01-09Epub Date: 2024-12-10DOI: 10.1016/j.xhgg.2024.100391
Abdoulaye Yalcouyé, Isabelle Schrauwen, Oumou Traoré, Salia Bamba, Elvis Twumasi Aboagye, Anushree Acharya, Thashi Bharadwaj, Rachel Latanich, Kevin Esoh, Cesar A Fortes-Lima, Carmen de Kock, Mario Jonas, Alassane Dit Baneye Maiga, Cheick A K Cissé, Moussa A Sangaré, Cheick O Guinto, Guida Landouré, Suzanne M Leal, Ambroise Wonkam
{"title":"Whole-exome sequencing reveals known and candidate genes for hearing impairment in Mali.","authors":"Abdoulaye Yalcouyé, Isabelle Schrauwen, Oumou Traoré, Salia Bamba, Elvis Twumasi Aboagye, Anushree Acharya, Thashi Bharadwaj, Rachel Latanich, Kevin Esoh, Cesar A Fortes-Lima, Carmen de Kock, Mario Jonas, Alassane Dit Baneye Maiga, Cheick A K Cissé, Moussa A Sangaré, Cheick O Guinto, Guida Landouré, Suzanne M Leal, Ambroise Wonkam","doi":"10.1016/j.xhgg.2024.100391","DOIUrl":"10.1016/j.xhgg.2024.100391","url":null,"abstract":"<p><p>Hearing impairment (HI) is the most common neurosensory disorder globally and is reported to be more prevalent in low-income countries. In high-income countries, up to 50% of congenital childhood HI is of genetic origin. However, there are limited genetic data on HI from sub-Saharan African populations. In this study, we investigated the genetic causes of HI in the Malian populations, using whole-exome sequencing. Furthermore, cDNA was transfected into HEK293T cells for localization and expression analysis in a candidate gene. Twenty-four multiplex families were enrolled, 50% (12/24) of which are consanguineous. Clustering methods showed patterns of admixture from non-African sources in some Malian populations. Variants were found in six known nonsyndromic HI (NSHI) genes, four genes that can underlie either syndromic HI (SHI) or NSHI, one SHI gene, and one novel candidate HI gene. Overall, 75% of families (18/24) were solved, and 94.4% (17/18) had variants in known HI genes including MYO15A, CDH23, MYO7A, GJB2, SLC26A4, PJVK, OTOGL, TMC1, CIB2, GAS2, PDCH15, and EYA1. A digenic inheritance (CDH23 and PDCH15) was found in one family. Most variants (59.1%, 13/22) in known HI genes were not previously reported or associated with HI. The UBFD1 candidate HI gene, which was identified in one consanguineous family, is expressed in human inner ear organoids. Cell-based experiments in HEK293T showed that mutants UBFD1 had a lower expression, compared to wild type. We report the profile of known genes and the UBFD1 candidate gene for HI in Mali and emphasize the potential of gene discovery in African populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100391"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2025-01-09Epub Date: 2024-10-10DOI: 10.1016/j.xhgg.2024.100371
Daniel Danis, Michael J Bamshad, Yasemin Bridges, Andrés Caballero-Oteyza, Pilar Cacheiro, Leigh C Carmody, Leonardo Chimirri, Jessica X Chong, Ben Coleman, Raymond Dalgleish, Peter J Freeman, Adam S L Graefe, Tudor Groza, Peter Hansen, Julius O B Jacobsen, Adam Klocperk, Maaike Kusters, Markus S Ladewig, Allison J Marcello, Teresa Mattina, Christopher J Mungall, Monica C Munoz-Torres, Justin T Reese, Filip Rehburg, Bárbara C S Reis, Catharina Schuetz, Damian Smedley, Timmy Strauss, Jagadish Chandrabose Sundaramurthi, Sylvia Thun, Kyran Wissink, John F Wagstaff, David Zocche, Melissa A Haendel, Peter N Robinson
{"title":"A corpus of GA4GH phenopackets: Case-level phenotyping for genomic diagnostics and discovery.","authors":"Daniel Danis, Michael J Bamshad, Yasemin Bridges, Andrés Caballero-Oteyza, Pilar Cacheiro, Leigh C Carmody, Leonardo Chimirri, Jessica X Chong, Ben Coleman, Raymond Dalgleish, Peter J Freeman, Adam S L Graefe, Tudor Groza, Peter Hansen, Julius O B Jacobsen, Adam Klocperk, Maaike Kusters, Markus S Ladewig, Allison J Marcello, Teresa Mattina, Christopher J Mungall, Monica C Munoz-Torres, Justin T Reese, Filip Rehburg, Bárbara C S Reis, Catharina Schuetz, Damian Smedley, Timmy Strauss, Jagadish Chandrabose Sundaramurthi, Sylvia Thun, Kyran Wissink, John F Wagstaff, David Zocche, Melissa A Haendel, Peter N Robinson","doi":"10.1016/j.xhgg.2024.100371","DOIUrl":"10.1016/j.xhgg.2024.100371","url":null,"abstract":"<p><p>The Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema was released in 2022 and approved by ISO as a standard for sharing clinical and genomic information about an individual, including phenotypic descriptions, numerical measurements, genetic information, diagnoses, and treatments. A phenopacket can be used as an input file for software that supports phenotype-driven genomic diagnostics and for algorithms that facilitate patient classification and stratification for identifying new diseases and treatments. There has been a great need for a collection of phenopackets to test software pipelines and algorithms. Here, we present Phenopacket Store. Phenopacket Store v.0.1.19 includes 6,668 phenopackets representing 475 Mendelian and chromosomal diseases associated with 423 genes and 3,834 unique pathogenic alleles curated from 959 different publications. This represents the first large-scale collection of case-level, standardized phenotypic information derived from case reports in the literature with detailed descriptions of the clinical data and will be useful for many purposes, including the development and testing of software for prioritizing genes and diseases in diagnostic genomics, machine learning analysis of clinical phenotype data, patient stratification, and genotype-phenotype correlations. This corpus also provides best-practice examples for curating literature-derived data using the GA4GH Phenopacket Schema.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100371"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2025-01-09Epub Date: 2024-11-14DOI: 10.1016/j.xhgg.2024.100383
Daiwei Zhang, Boran Gao, Qidi Feng, Ani Manichaikul, Gina M Peloso, Russell P Tracy, Peter Durda, Kent D Taylor, Yongmei Liu, W Craig Johnson, Stacey Gabriel, Namrata Gupta, Joshua D Smith, Francois Aguet, Kristin G Ardlie, Thomas W Blackwell, Robert E Gerszten, Stephen S Rich, Jerome I Rotter, Laura J Scott, Xiang Zhou, Seunggeun Lee
{"title":"Proteome-wide association studies for blood lipids and comparison with transcriptome-wide association studies.","authors":"Daiwei Zhang, Boran Gao, Qidi Feng, Ani Manichaikul, Gina M Peloso, Russell P Tracy, Peter Durda, Kent D Taylor, Yongmei Liu, W Craig Johnson, Stacey Gabriel, Namrata Gupta, Joshua D Smith, Francois Aguet, Kristin G Ardlie, Thomas W Blackwell, Robert E Gerszten, Stephen S Rich, Jerome I Rotter, Laura J Scott, Xiang Zhou, Seunggeun Lee","doi":"10.1016/j.xhgg.2024.100383","DOIUrl":"10.1016/j.xhgg.2024.100383","url":null,"abstract":"<p><p>Blood lipid traits are treatable and heritable risk factors for heart disease, a leading cause of mortality worldwide. Although genome-wide association studies (GWASs) have discovered hundreds of variants associated with lipids in humans, most of the causal mechanisms of lipids remain unknown. To better understand the biological processes underlying lipid metabolism, we investigated the associations of plasma protein levels with total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol in blood. We trained protein prediction models based on samples in the Multi-Ethnic Study of Atherosclerosis (MESA) and applied them to conduct proteome-wide association studies (PWASs) for lipids using the Global Lipids Genetics Consortium (GLGC) data. Of the 749 proteins tested, 42 were significantly associated with at least one lipid trait. Furthermore, we performed transcriptome-wide association studies (TWASs) for lipids using 9,714 gene expression prediction models trained on samples from peripheral blood mononuclear cells (PBMCs) in MESA and 49 tissues in the Genotype-Tissue Expression (GTEx) project. We found that although PWASs and TWASs can show different directions of associations in an individual gene, 40 out of 49 tissues showed a positive correlation between PWAS and TWAS signed p values across all the genes, which suggests high-level consistency between proteome-lipid associations and transcriptome-lipid associations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100383"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-10-10Epub Date: 2024-08-30DOI: 10.1016/j.xhgg.2024.100345
James Chettle, Raymond J Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R Curtis Rogers, Barbara R DuPont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M Wentzensen, Blake Vuocolo, Seema R Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J Sanders, Sarah P Blagden
{"title":"LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder.","authors":"James Chettle, Raymond J Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R Curtis Rogers, Barbara R DuPont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M Wentzensen, Blake Vuocolo, Seema R Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J Sanders, Sarah P Blagden","doi":"10.1016/j.xhgg.2024.100345","DOIUrl":"10.1016/j.xhgg.2024.100345","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100345"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-10-10Epub Date: 2024-08-12DOI: 10.1016/j.xhgg.2024.100340
Laura M Schultz, Alexys Knighton, Guillaume Huguet, Zohra Saci, Martineau Jean-Louis, Josephine Mollon, Emma E M Knowles, David C Glahn, Sébastien Jacquemont, Laura Almasy
{"title":"Copy-number variants differ in frequency across genetic ancestry groups.","authors":"Laura M Schultz, Alexys Knighton, Guillaume Huguet, Zohra Saci, Martineau Jean-Louis, Josephine Mollon, Emma E M Knowles, David C Glahn, Sébastien Jacquemont, Laura Almasy","doi":"10.1016/j.xhgg.2024.100340","DOIUrl":"10.1016/j.xhgg.2024.100340","url":null,"abstract":"<p><p>Copy-number variants (CNVs) have been implicated in a variety of neuropsychiatric and cognitive phenotypes. We found that deleterious CNVs are less prevalent in non-European ancestry groups than they are in European ancestry groups of both the UK Biobank (UKBB) and a US replication cohort (SPARK). We also identified specific recurrent CNVs that consistently differ in frequency across ancestry groups in both the UKBB and SPARK. These ancestry-related differences in CNV prevalence present in both an unselected community population and a family cohort enriched with individuals diagnosed with autism spectrum disorder (ASD) strongly suggest that genetic ancestry should be considered when probing associations between CNVs and health outcomes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100340"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11401192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-10-10Epub Date: 2024-07-22DOI: 10.1016/j.xhgg.2024.100335
Kevin Uguen, Marlène Le Tertre, Dimitri Tchernitchko, Ahmad Elbahnsi, Sandrine Maestri, Isabelle Gourlaouen, Claude Férec, Chandran Ka, Isabelle Callebaut, Gérald Le Gac
{"title":"The dual loss and gain of function of the FPN1 iron exporter results in the ferroportin disease phenotype.","authors":"Kevin Uguen, Marlène Le Tertre, Dimitri Tchernitchko, Ahmad Elbahnsi, Sandrine Maestri, Isabelle Gourlaouen, Claude Férec, Chandran Ka, Isabelle Callebaut, Gérald Le Gac","doi":"10.1016/j.xhgg.2024.100335","DOIUrl":"10.1016/j.xhgg.2024.100335","url":null,"abstract":"<p><p>Heterozygous mutations in SLC40A1, encoding a multi-pass membrane protein of the major facilitator superfamily known as ferroportin 1 (FPN1), are responsible for two distinct hereditary iron-overload diseases: ferroportin disease, which is associated with reduced FPN1 activity (i.e., decrease in cellular iron export), and SLC40A1-related hemochromatosis, which is associated with abnormally high FPN1 activity (i.e., resistance to hepcidin). Here, we report three SLC40A1 missense variants with opposite functional consequences. In cultured cells, the p.Arg40Gln and p.Ser47Phe substitutions partially reduced the ability of FPN1 to export iron and also partially reduced its sensitivity to hepcidin. The p.Ala350Val substitution had more profound effects, resulting in low FPN1 iron egress and weak FPN1/hepcidin interaction. Structural analyses helped to differentiate the first two substitutions, which are predicted to cause local instabilities, and the third, which is thought to prevent critical rigid-body movements that are essential to the iron transport cycle. The phenotypic traits observed in a total of 12 affected individuals are highly suggestive of ferroportin disease. Our findings dismantle the classical dualism of FPN1 loss versus gain of function, highlight some specific and unexpected functions of FPN1 transmembrane helices in the molecular mechanism of iron export and its regulation by hepcidin, and extend the spectrum of rare genetic variants that may cause ferroportin disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100335"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-10-10Epub Date: 2024-08-22DOI: 10.1016/j.xhgg.2024.100343
Iman Hamid, Séverine Nantenaina Stéphie Raveloson, Germain Jules Spiral, Soanorolalao Ravelonjanahary, Brigitte Marie Raharivololona, José Mahenina Randria, Mosa Zafimaro, Tsiorimanitra Aimée Randriambola, Rota Mamimbahiny Andriantsoa, Tojo Julio Andriamahefa, Bodonomena Fitahiana Laza Rafidison, Mehreen Mughal, Anne-Katrin Emde, Melissa Hendershott, Sarah LeBaron von Baeyer, Kaja A Wasik, Jean Freddy Ranaivoarisoa, Laura Yerges-Armstrong, Stephane E Castel, Rindra Rakotoarivony
{"title":"Mid-pass whole-genome sequencing in a Malagasy cohort uncovers body composition associations.","authors":"Iman Hamid, Séverine Nantenaina Stéphie Raveloson, Germain Jules Spiral, Soanorolalao Ravelonjanahary, Brigitte Marie Raharivololona, José Mahenina Randria, Mosa Zafimaro, Tsiorimanitra Aimée Randriambola, Rota Mamimbahiny Andriantsoa, Tojo Julio Andriamahefa, Bodonomena Fitahiana Laza Rafidison, Mehreen Mughal, Anne-Katrin Emde, Melissa Hendershott, Sarah LeBaron von Baeyer, Kaja A Wasik, Jean Freddy Ranaivoarisoa, Laura Yerges-Armstrong, Stephane E Castel, Rindra Rakotoarivony","doi":"10.1016/j.xhgg.2024.100343","DOIUrl":"10.1016/j.xhgg.2024.100343","url":null,"abstract":"<p><p>The majority of human genomic research studies have been conducted in European-ancestry cohorts, reducing the likelihood of detecting potentially novel and globally impactful findings. Here, we present mid-pass whole-genome sequencing data and a genome-wide association study in a cohort of 264 self-reported Malagasy individuals from three locations on the island of Madagascar. We describe genetic variation in this Malagasy cohort, providing insight into the shared and unique patterns of genetic variation across the island. We observe phenotypic variation by location and find high rates of hypertension, particularly in the Southern Highlands sampling site, as well as elevated self-reported malaria prevalence in the West Coast site relative to other sites. After filtering to a subset of 214 minimally related individuals, we find a number of genetic associations with body composition traits, including many variants that are only observed in African populations or populations with admixed African ancestry from the 1000 Genomes Project. This study highlights the importance of including diverse populations in genomic research for the potential to gain novel insights, even with small cohort sizes. This project was conducted in partnership and consultation with local stakeholders in Madagascar and serves as an example of genomic research that prioritizes community engagement and potentially impacts our understanding of human health and disease.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100343"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11415767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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