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Article ; Online: The role of interleukin-2, all-trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma.

Nguyen, Rosa / Houston, Jim / Chan, Wing K / Finkelstein, David / Dyer, Michael A

2018 Volume 67, Issue 4, Page(s) 615–626

Abstract: Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve ... ...

Abstract	Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood. We developed a quantitative assay to test ADCC induced by the anti-GD2 antibody Hu14.18K322A in nine neuroblastoma cell lines and dissociated cells from orthotopic patient-derived xenografts (O-PDXs) in culture. IL-2 improved ADCC against neuroblastoma cells, and differentiation with all-trans retinoic acid stabilized GD2 expression on tumor cells and enhanced ADCC as well. Degranulation was highest in licensed NK cells that expressed CD158b (P < 0.001) and harbored a killer-cell immunoglobulin-like receptor (KIR) mismatch against the tumor-specific human leukocyte antigen (HLA; P = 0.016). In conclusion, IL-2 is an important component of immunotherapy because it can improve the cytolytic function of NK cells against neuroblastoma cells and could lower the antibody dose required for efficacy, thereby reducing toxicity. The effect of IL-2 may vary among individuals and a biomarker would be useful to predict ADCC following IL-2 activation. Sub-populations of NK cells may have different levels of activity dependent on their licensing status, KIR expression, and HLA-KIR interaction. Better understanding of HLA-KIR interactions and the molecular changes following retinoid-induced differentiation is necessary to delineate their role in ADCC.
MeSH term(s)	Antibodies, Monoclonal/administration & dosage ; Antibody-Dependent Cell Cytotoxicity/immunology ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Combined Modality Therapy ; Gangliosides/immunology ; Humans ; Interleukin-2/administration & dosage ; Killer Cells, Natural/immunology ; Neuroblastoma/immunology ; Neuroblastoma/pathology ; Neuroblastoma/therapy ; Tretinoin/administration & dosage ; Tumor Cells, Cultured
Chemical Substances	Antibodies, Monoclonal ; Gangliosides ; Interleukin-2 ; Tretinoin (5688UTC01R) ; ganglioside, GD2 (65988-71-8)
Language	English
Publishing date	2018-01-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-017-2108-6
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Article ; Online: Psychological Distress and Quality of Life in Participants Undergoing Genetic Testing for Arrhythmogenic Right Ventricular Cardiomyopathy Caused by TMEM43 p.S358L: Is It Time to Offer Population-Based Genetic Screening?

Brothers, Cassidy / Etchegary, Holly / Curtis, Fiona / Simmonds, Charlene / Houston, Jim / Young, Terry-Lynn / Pullman, Daryl / Mariathas, Hensley H / Connors, Sean / Hodgkinson, Kathleen

Public health genomics

2021 Volume 24, Issue 5-6, Page(s) 253–260

Abstract: Purpose: We have identified 27 families in Newfoundland and Labrador (NL) with the founder variant TMEM43 p.S358L responsible for 1 form of arrhythmogenic right ventricular cardiomyopathy. Current screening guidelines rely solely on cascade genetic ... ...

Abstract	Purpose: We have identified 27 families in Newfoundland and Labrador (NL) with the founder variant TMEM43 p.S358L responsible for 1 form of arrhythmogenic right ventricular cardiomyopathy. Current screening guidelines rely solely on cascade genetic screening, which may result in unrecognized, high-risk carriers who would benefit from preemptive implantable cardioverter-defibrillator therapy. This pilot study explored the acceptability among subjects to TMEM43 p.S358L population-based genetic screening (PBGS) in this Canadian province. Methods: A prospective cohort study assessed attitudes, psychological distress, and health-related quality of life (QOL) in unselected individuals who underwent genetic screening for the TMEM43 p.S358L variant. Participants (n = 73) were recruited via advertisements and completed 2 surveys at baseline, 6 months, and 1 year which measured health-related QOL (SF-36v2) and psychological distress (Impact of Events Scale). Results: No variant-positive carriers were identified. Of those screened through a telephone questionnaire, >95% felt positive about population-genetic screening for TMEM43 p.S358L, though 68% reported some degree of anxiety after seeing the advertisement. There were no significant changes in health-related QOL or psychological distress scores over the study period. Conclusion: Despite some initial anxiety, we show support for PBGS among research subjects who screened negative for the TMEM43 p.S358L variant in NL. These findings have implications for future PBGS programs in the province.
MeSH term(s)	Arrhythmogenic Right Ventricular Dysplasia/diagnosis ; Arrhythmogenic Right Ventricular Dysplasia/genetics ; Canada ; Genetic Testing ; Humans ; Membrane Proteins/genetics ; Pilot Projects ; Prospective Studies ; Psychological Distress ; Quality of Life
Chemical Substances	Membrane Proteins ; TMEM43 protein, human
Language	English
Publishing date	2021-09-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2457023-0
ISSN	1662-8063 ; 1662-4246
ISSN (online)	1662-8063
ISSN	1662-4246
DOI	10.1159/000517265
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Article ; Online: Highly variable hearing loss due to POU4F3 (c.37del) is revealed by longitudinal, frequency specific analyses.

European journal of human genetics : EJHG

2023 Volume 31, Issue 7, Page(s) 815–823

Abstract: Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype ... ...

Abstract	Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.
MeSH term(s)	Humans ; Cross-Sectional Studies ; Homeodomain Proteins/genetics ; Hearing Loss/genetics ; Hearing Loss, Sensorineural/diagnosis ; Hearing Loss, Sensorineural/genetics ; Hearing Loss, Sensorineural/pathology ; Deafness ; Pedigree ; Transcription Factor Brn-3C/genetics
Chemical Substances	Homeodomain Proteins ; POU4F3 protein, human ; Transcription Factor Brn-3C
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-023-01358-0
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Article ; Online: Next-generation humanized patient-derived xenograft mouse model for pre-clinical antibody studies in neuroblastoma.

Nguyen, Rosa / Patel, Anand G / Griffiths, Lyra M / Dapper, Jason / Stewart, Elizabeth A / Houston, Jim / Johnson, Melissa / Akers, Walter J / Furman, Wayne L / Dyer, Michael A

Cancer immunology, immunotherapy : CII

2020 Volume 70, Issue 3, Page(s) 721–732

Abstract: Faithful tumor mouse models are fundamental research tools to advance the field of immuno-oncology (IO). This is particularly relevant in diseases with low incidence, as in the case of pediatric malignancies, that rely on pre-clinical therapeutic ... ...

Abstract	Faithful tumor mouse models are fundamental research tools to advance the field of immuno-oncology (IO). This is particularly relevant in diseases with low incidence, as in the case of pediatric malignancies, that rely on pre-clinical therapeutic development. However, conventional syngeneic and genetically engineered mouse models fail to recapitulate the tumor heterogeneity and microenvironmental complexity of human pathology that are essential determinants of cancer-directed immunity. Here, we characterize a novel mouse model that supports human natural killer (NK) cell development and engraftment of neuroblastoma orthotopic patient-derived xenograft (O-PDX) for pre-clinical antibody and cytokine testing. Using cytotoxicity assays, single-cell RNA-sequencing, and multi-color flow cytometry, we demonstrate that NK cells that develop in the humanized mice are fully licensed to execute NK cell cytotoxicity, permit human tumor engraftment, but can be therapeutically redirected to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Although these cells share phenotypic and molecular features with healthy controls, we noted that they lacked an NK cell subset, termed activated NK cells, that is characterized by differentially expressed genes that are induced by cytokine activation. Because this subset of genes is also downregulated in patients with neuroblastoma compared to healthy controls, we hypothesize that this finding could be due to tumor-mediated suppressive effects. Thus, despite its technical complexity, this humanized patient-derived xenograft mouse model could serve as a faithful system for future testing of IO applications and studies of underlying immunologic processes.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibody-Dependent Cell Cytotoxicity/immunology ; Antineoplastic Agents, Immunological/pharmacology ; Bone Marrow Transplantation ; Case-Control Studies ; Cell Line, Tumor ; Combined Modality Therapy ; Disease Models, Animal ; Female ; Humans ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Male ; Mice ; Neuroblastoma/drug therapy ; Neuroblastoma/immunology ; Neuroblastoma/pathology ; Treatment Outcome ; Xenograft Model Antitumor Assays
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological
Language	English
Publishing date	2020-09-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-020-02713-6
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Article ; Online: The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate.

Green, Jane S / O'Rielly, Darren D / Pater, Justin A / Houston, Jim / Rajabi, Hoda / Galutira, Dante / Benteau, Tammy / Sheaves, Amy / Abdelfatah, Nelly / Bautista, Donna / Whelan, Jim / Young, Terry-Lynn

European journal of human genetics : EJHG

2020 Volume 28, Issue 7, Page(s) 925–937

Abstract: Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 ... ...

Abstract	Stargardt disease (STGD1) is a form of inherited retinal dystrophy attributed to variants affecting function of the large ABCA4 gene and is arguably the most complex monogenic disease. Therapeutic trials in patients depend on identifying causal ABCA4 variants in trans, which is complicated by extreme allelic and clinical heterogeneity. We report the genetic architecture of STGD1 in the young genetically isolated population of Newfoundland, Canada. Population-based clinical recruitment over several decades yielded 29 STGD1 and STGD1-like families (15 multiplex, 14 singleton). Family interviews and public archival records reveal the vast majority of pedigree founders to be of English extraction. Full gene sequencing and haplotype analysis yielded a high solve rate (38/41 cases; 92.7%) for STGD1 and identified 16 causative STGD1 alleles, including a novel deletion (NM_000350.3: ABCA4 c.67-1delG). Several STGD1 alleles of European origin (including NM_000350.3: ABCA4 c.5714 + 5G>A and NM_000350.3: ABCA4 c.5461-10T>C) have drifted to a relatively high population frequency due to founder effect. We report on retinal disease progression in homozygous patients, providing valuable allele-specific insights. The least involved retinal disease is seen in patients homozygous for c.5714 + 5G>A variant, a so-called "mild" variant which is sufficient to precipitate a STGD1 phenotype in the absence of other pathogenic variants in the coding region and intron/exon boundaries of ABCA4. The most severe retinal disease is observed in cases with ABCA4 c.[5461-10T>C;5603A>T] complex allele. We discuss the advantages of determining genetic architecture in genetic isolates in order to begin to meet the grand challenge of human genetics.
MeSH term(s)	ATP-Binding Cassette Transporters/genetics ; Female ; Founder Effect ; Gene Frequency ; Homozygote ; Humans ; Male ; Mutation ; Pedigree ; Stargardt Disease/genetics
Chemical Substances	ABCA4 protein, human ; ATP-Binding Cassette Transporters
Language	English
Publishing date	2020-05-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-020-0581-4
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Article ; Online: Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss.

Pater, Justin A / Green, Jane / O'Rielly, Darren D / Griffin, Anne / Squires, Jessica / Burt, Taylor / Fernandez, Sara / Fernandez, Bridget / Houston, Jim / Zhou, Jiayi / Roslin, Nicole M / Young, Terry-Lynn

BMC medical genetics

2019 Volume 20, Issue 1, Page(s) 68

Abstract: Background: Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients ... ...

Abstract	Background: Usher syndrome, the most common form of inherited deaf-blindness, is unlike many other forms of syndromic hereditary hearing loss in that the extra aural clinical manifestations are also detrimental to communication. Usher syndrome patients with early onset deafness also experience vision loss due to progressive retinitis pigmentosa that can lead to legal blindness in their third or fourth decade. Methods: Using a multi-omic approach, we identified three novel pathogenic variants in two Usher syndrome genes (USH2A and ADGRV1) in cases initially referred for isolated vision or hearing loss. Results: In a multiplex hearing loss family, two affected sisters, the product of a second cousin union, are homozygous for a novel nonsense pathogenic variant in ADGRV1 (c.17062C > T, p.Arg5688), predicted to create a premature stop codon near the N-terminus of ADGRV1. Ophthalmological examination of the sisters confirmed typical retinitis pigmentosa and prompted a corrected Usher syndrome diagnosis. In an unrelated clinical case, a child with hearing loss tested positive for two novel USH2A splicing variants (c.5777-1G > A, p. Glu1926_Ala1952del and c.10388-2A > G, p.Asp3463Alafs6) and RNA studies confirmed that both pathogenic variants cause splicing errors. Interestingly, these same USH2A variants are also identified in another family with vision loss where subsequent clinical follow-up confirmed pre-existing hearing loss since early childhood, eventually resulting in a reassigned diagnosis of Usher syndrome. Conclusion: These findings provide empirical evidence to increase Usher syndrome surveillance of at-risk children. Given that novel antisense oligonucleotide therapies have been shown to rescue retinal degeneration caused by USH2A splicing pathogenic variants, these solved USH2A patients may now be eligible to be enrolled in therapeutic trials.
MeSH term(s)	Child ; Child, Preschool ; Deaf-Blind Disorders/genetics ; Female ; Genotype ; Humans ; Male ; Pedigree ; Phenotype ; Usher Syndromes/genetics
Language	English
Publishing date	2019-05-02
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2350
ISSN (online)	1471-2350
DOI	10.1186/s12881-019-0777-z
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Article ; Online: Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene.

Pater, Justin A / Penney, Cindy / O'Rielly, Darren D / Griffin, Anne / Kamal, Lara / Brownstein, Zippora / Vona, Barbara / Vinkler, Chana / Shohat, Mordechai / Barel, Ortal / French, Curtis R / Singh, Sushma / Werdyani, Salem / Burt, Taylor / Abdelfatah, Nelly / Houston, Jim / Doucette, Lance P / Squires, Jessica / Glaser, Fabian /

Roslin, Nicole M / Vincent, Daniel / Marquis, Pascale / Woodland, Geoffrey / Benoukraf, Touati / Hawkey-Noble, Alexia / Avraham, Karen B / Stanton, Susan G / Young, Terry-Lynn

Human genetics

2022 Volume 141, Issue 3-4, Page(s) 431–444

Abstract: Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of ... ...

Abstract	Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.
MeSH term(s)	Humans ; 3' Untranslated Regions ; ATP-Binding Cassette Transporters/genetics ; Deafness/genetics ; Hearing Loss/genetics ; Hearing Loss, Sensorineural/genetics ; Mutation ; Pedigree ; Phospholipids/metabolism ; RNA Splice Sites
Chemical Substances	3' Untranslated Regions ; ATP-Binding Cassette Transporters ; ATP11A protein, human (EC 7.6.2.1) ; Phospholipids ; RNA Splice Sites
Language	English
Publishing date	2022-03-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-022-02444-x
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Article ; Online: TOX2 regulates human natural killer cell development by controlling T-BET expression.

Vong, Queenie P / Leung, Wai-Hang / Houston, Jim / Li, Ying / Rooney, Barbara / Holladay, Martha / Oostendorp, Robert A J / Leung, Wing

Blood

2014 Volume 124, Issue 26, Page(s) 3905–3913

Abstract: Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA-binding domain with the other TOX members. Although TOX1 ... ...

Abstract	Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA-binding domain with the other TOX members. Although TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells (mNK) and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)-derived CD34(+) cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, whereas overexpression of TOX2 enhanced the development of mNK cells from UCB CD34(+) cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation.
MeSH term(s)	Animals ; Antigens, CD34/metabolism ; Cell Differentiation ; Fetal Blood/cytology ; Gene Expression Regulation, Developmental ; Gene Silencing ; HEK293 Cells ; HMGB Proteins/metabolism ; Humans ; Killer Cells, Natural/cytology ; Lentivirus/metabolism ; Liver/embryology ; Lymphocytes/cytology ; Mice ; Mice, Inbred NOD ; Oligonucleotide Array Sequence Analysis ; Protein Binding ; Protein Structure, Tertiary ; T-Box Domain Proteins/metabolism ; Transcription, Genetic
Chemical Substances	Antigens, CD34 ; HMGB Proteins ; T-Box Domain Proteins ; T-box transcription factor TBX21 ; Tox2 protein, human
Language	English
Publishing date	2014-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2014-06-582965
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Article ; Online: A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.

Abdelfatah, Nelly / Mostafa, Ahmed A / French, Curtis R / Doucette, Lance P / Penney, Cindy / Lucas, Matthew B / Griffin, Anne / Booth, Valerie / Rowley, Christopher / Besaw, Jessica E / Tranebjærg, Lisbeth / Rendtorff, Nanna Dahl / Hodgkinson, Kathy A / Little, Leichelle A / Agrawal, Sumit / Parnes, Lorne / Batten, Tony / Moore, Susan / Hu, Pingzhao /

Pater, Justin A / Houston, Jim / Galutira, Dante / Benteau, Tammy / MacDonald, Courtney / French, Danielle / O'Rielly, Darren D / Stanton, Susan G / Young, Terry-Lynn

Human genetics

2021 Volume 141, Issue 3-4, Page(s) 965–979

Abstract: Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped ... ...

Abstract	Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.
MeSH term(s)	Forkhead Transcription Factors/genetics ; Humans ; Otosclerosis/genetics
Chemical Substances	FOXL1 protein, human ; Forkhead Transcription Factors
Language	English
Publishing date	2021-10-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-021-02381-1
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Article ; Online: A novel deletion in SMPX causes a rare form of X-linked progressive hearing loss in two families due to a founder effect.

Abdelfatah, Nelly / Merner, Nancy / Houston, Jim / Benteau, Tammy / Griffin, Anne / Doucette, Lance / Stockley, Tracy / Lauzon, Julie L / Young, Terry-Lynn

Human mutation

2013 Volume 34, Issue 1, Page(s) 66–69

Abstract: X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of ... ...

Abstract	X-linked hearing loss is the rarest form of genetic hearing loss contributing to <1% of cases. We identified a multiplex family from Newfoundland (Family 2024) segregating X-linked hearing loss. Haplotyping of the X chromosome and sequencing of positional candidate genes revealed a novel point deletion (c.99delC) in SMPX which encodes a small muscle protein responsible for reducing mechanical stress during muscle contraction. This novel deletion causes a frameshift and a premature stop codon (p.Arg34GlufsX47). We successfully sequenced both SMPX wild-type and mutant alleles from cDNA of a lymphoblastoid cell line, suggesting that the mutant allele may not be degraded via nonsense-mediated mRNA decay. To investigate the role of SMPX in other subpopulations, we fully sequenced SMPX in 229 Canadian probands with hearing loss and identified a second Newfoundland Family (2196) with the same mutation, and a shared haplotype on the X chromosome, suggesting a common ancestor.
MeSH term(s)	Base Sequence ; DNA Mutational Analysis ; Exons/genetics ; Family Health ; Female ; Founder Effect ; Genetic Diseases, X-Linked/genetics ; Hearing Loss/genetics ; Humans ; Male ; Muscle Proteins/genetics ; Pedigree ; Sequence Deletion
Chemical Substances	Muscle Proteins ; SMPX protein, human
Language	English
Publishing date	2013-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.22205
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