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Genetics

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TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells
Mayara Garcia de Mattos Barbosa, … , Jeffrey L. Platt, Marilia Cascalho
Mayara Garcia de Mattos Barbosa, … , Jeffrey L. Platt, Marilia Cascalho
Published July 20, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.150483.
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TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells

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Abstract

Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNFRSF13B variants which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells’ functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of the subjects with antibody-mediated rejection (AMR) but less than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses we investigated allo-immunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice was not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased “natural” IgM and compromised complement regulation leading to complement deposition in allografted hearts and autogenous kidneys. Thus, wild type TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes, intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhances morbidity associated with immune responses.

Authors

Mayara Garcia de Mattos Barbosa, Adam R. Lefferts, Daniel Huynh, Hui Liu, Yu Zhang, Beverly Fu, Jenna Barnes, Milagros Samaniego, Richard J. Bram, Raif Geha, Ariella Shikanov, Eline T. Luning Prak, Evan A. Farkash, Jeffrey L. Platt, Marilia Cascalho

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Gene expression atlas of energy balance brain regions
Maria Caterina De Rosa, … , Judith Y. Altarejos, Claudia A. Doege
Maria Caterina De Rosa, … , Judith Y. Altarejos, Claudia A. Doege
Published July 20, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.149137.
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Gene expression atlas of energy balance brain regions

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Abstract

Energy balance is controlled by interconnected brain regions in the hypothalamus, brain stem, cortex and limbic system. Gene expression signatures of these regions can help elucidate the pathophysiology underlying obesity. RNA sequencing was conducted on P56 C57BL/6NTac male mice and E14.5 C57BL/6NTac embryos punch-biopsies in 16 obesity-relevant brain regions. The expression of 190 known obesity-associated genes (monogenic, rare and low-frequency coding variants, genome-wide association studies (GWAS), syndromic) were analyzed in each anatomical region. Genes associated with these genetic categories of obesity had localized expression patterns across brain regions. Known monogenic obesity causal genes were highly enriched in the arcuate nucleus of the hypothalamus and developing hypothalamus. The obesity-associated genes clustered into distinct ‘modules’ of similar expression profile and these are distinct from expression ‘modules’ formed by similar analysis with genes known to be associated with other disease phenotypes (type 1 and type 2 diabetes, autism, breast cancer) in the same energy balance-relevant brain regions.

Authors

Maria Caterina De Rosa, Hannah J. Glover, George Stratigopoulos, Charles A. LeDuc, Qi Su, Yufeng Shen, Mark W. Sleeman, Wendy K. Chung, Rudolph L. Leibel, Judith Y. Altarejos, Claudia A. Doege

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A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome
Damien Abreu, … , Tamara Hershey, Fumihiko Urano
Damien Abreu, … , Tamara Hershey, Fumihiko Urano
Published June 29, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.145188.
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A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome

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Abstract

BACKGROUND. Wolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS. Based on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic beta-cell functions, visual acuity, quality of life measures related to vision, and neurological functions. RESULTS. The results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Overall, β-cell functions were not significantly improved by dantrolene, but there was a significant correlation between baseline β-cell functions and the change in β-cell responsiveness (R2, p=0.004) after 6 months of dantrolene therapy. Other outcome measures, including visual acuity and neurological functions, were not improved by dantrolene sodium treatment within 6 months. As previously reported, markers of inflammatory cytokines and oxidative stress, such as IFNγ, IL-1β, TNFα, and isoprostane, were elevated in subjects with Wolfram syndrome. CONCLUSION. This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome. TRIAL REGISTRATION. ClinicalTrials.gov Identifier NCT02829268

Authors

Damien Abreu, Stephen I. Stone, Toni S. Pearson, Robert C. Bucelli, Ashley N. Simpson, Stacy Hurst, Cris M. Brown, Kelly Kries, Chinyere Onwumere, Hongjie Gu, James Hoekel, Lawrence Tychsen, Gregory P. Van Stavern, Neil H. White, Bess A. Marshall, Tamara Hershey, Fumihiko Urano

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Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission
Camila Pará, … , Graziella Di Cristo, Alexey V. Pshezhetsky
Camila Pará, … , Graziella Di Cristo, Alexey V. Pshezhetsky
Published June 22, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.142073.
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Early defects in mucopolysaccharidosis type IIIC disrupt excitatory synaptic transmission

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Abstract

The majority of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPSIIIC), the major burdens are progressive and severe neuropsychiatric problems and dementia primarily thought to stem from neurodegeneration. Using the MPSIIIC mouse model we studied whether clinical manifestations preceding massive neurodegeneration arise from synaptic dysfunction. Reduced levels or abnormal distribution of multiple synaptic proteins were revealed in cultured hippocampal and CA1 pyramidal MPSIIIC neurons. These defects were rescued by virus-mediated gene correction. Dendritic spines were reduced in pyramidal neurons of mouse models of MPSIIIC and other (Tay-Sachs, sialidosis) LSD as early as postnatal day 10. MPSIIIC neurons also presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganised microtubule networks and partially impaired axonal transport of synaptic proteins. Furthermore, postsynaptic densities were reduced in post-mortem cortices of human MPS patients suggesting that the pathology is a common hallmark for neurological LSD. Together, our results demonstrate that lysosomal storage defects cause early alterations in synaptic structure and abnormalities in neurotransmission originating from impaired synaptic vesicular transport, and suggest that synaptic defects could be targeted to treat behavioral and cognitive defects in neurological LSD patients.

Authors

Camila Pará, Poulomee Bose, Luigi Bruno, Erika Freemantle, Mahsa Taherzadeh, Xuefang Pan, Chanshuai Han, Peter S. McPherson, Jean-Claude Lacaille, Éric Bonneil, Pierre Thibault, Claire O'Leary, Brian Bigger, Carlos Ramon Morales, Graziella Di Cristo, Alexey V. Pshezhetsky

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Longitudinal genotype-phenotype analysis in 86 PAX6-related aniridia patients
Vivienne Kit, … , Ahmed M. Hagag, Mariya Moosajee
Vivienne Kit, … , Ahmed M. Hagag, Mariya Moosajee
Published June 8, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.148406.
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Longitudinal genotype-phenotype analysis in 86 PAX6-related aniridia patients

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Abstract

Aniridia is most commonly caused by haploinsufficiency of the PAX6 gene, characterised by variable iris and foveal hypoplasia, nystagmus, cataracts, glaucoma and aniridia related keratopathy (ARK). Genotype-phenotype correlations have previously been described, however detailed longitudinal studies of aniridia are less commonly reported. We identified eighty-six patients from sixty-two unrelated families with molecularly confirmed heterozygous PAX6 variants from a United Kingdom (UK)-based single-centre ocular genetics service. They were categorised into mutation groups and retrospective review of baseline to most recent clinical characteristics (ocular and systemic) were recorded. One hundred and seventy-two eyes were evaluated, with a mean follow up period of 16.3 ± 12.7 years. Nystagmus was recorded in 87.2%, and foveal hypoplasia in 75%. Cataracts were diagnosed in 70.3%, glaucoma in 20.6% and ARK in 68.6% of eyes. Prevalence, age of diagnosis and surgical intervention varied amongst mutation groups. Overall, the missense mutation sub-group had the mildest phenotype, and surgically naïve eyes maintained better visual acuity. Systemic evaluation identified type 2 diabetes in 12.8%, which is twice the UK prevalence. This is the largest longitudinal study of aniridia in the United Kingdom, providing insights into prognostic indicators for patients and guiding clinical management of both ocular and systemic features.

Authors

Vivienne Kit, Dulce Lima Cunha, Ahmed M. Hagag, Mariya Moosajee

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A KCNK16 mutation causing TALK-1 gain-of-function is associated with maturity-onset diabetes of the young
Sarah M. Graff, … , David A. Jacobson, Emma L. Duncan
Sarah M. Graff, … , David A. Jacobson, Emma L. Duncan
Published May 25, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.138057.
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A KCNK16 mutation causing TALK-1 gain-of-function is associated with maturity-onset diabetes of the young

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Abstract

Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β-cell function. One of the mechanisms results from β-cell KATP channel dysfunction (e.g., KCNJ11 (MODY13) or ABCC8 (MODY12) mutations); however, no other β-cell channelopathies have been identified in MODY. We identified a previously unreported non-synonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β-cell-restricted K+ channel transcript and encodes the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain-of-function with TALK-1 Leu114Pro vs. WT, due to greater single channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx was inhibited in mouse islets expressing TALK-1 Leu114Pro (area under the Ca2+ curve [AUC] at 20mM glucose: Leu114Pro 60.1 vs. WT 89.1; P=0.030) with less endoplasmic reticulum Ca2+ storage (cyclopiazonic acid-induced release AUC: Leu114Pro 17.5 vs. WT 46.8; P=0.008). TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared to TALK-1 WT in mouse (52% decrease, P=0.039) and human (38% decrease, P=0.019) islets. These data suggest KCNK16 is a previously unreported gene for MODY.

Authors

Sarah M. Graff, Stephanie R. Johnson, Paul J. Leo, Prasanna K. Dadi, Matthew T. Dickerson, Arya Y. Nakhe, Aideen M. McInerney-Leo, Mhairi Marshall, Karolina E. Zaborska, Charles M. Schaub, Matthew A. Brown, David A. Jacobson, Emma L. Duncan

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TPP1 mutagenesis screens unravel shelterin interfaces and functions in hematopoiesis
Sherilyn Grill, … , Ivan Maillard, Jayakrishnan Nandakumar
Sherilyn Grill, … , Ivan Maillard, Jayakrishnan Nandakumar
Published April 6, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.138059.
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TPP1 mutagenesis screens unravel shelterin interfaces and functions in hematopoiesis

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Abstract

Telomerase catalyzes chromosome end replication in stem cells and other long-lived cells. Mutations in telomerase or telomere-related genes result in diseases known as telomeropathies. Telomerase is recruited to chromosome ends by the ACD/TPP1 protein (TPP1 hereafter), a component of the shelterin complex that protects chromosome ends from unwanted end-joining. TPP1 facilitates end-protection by binding shelterin proteins POT1 and TIN2. TPP1 variants have been associated with telomeropathies, but remain poorly characterized in vivo. Disease variants and mutagenesis scans provide efficient avenues to interrogate the distinct physiological roles of TPP1. Here, we conduct mutagenesis in the TIN2- and POT1-binding domains of TPP1 to discover mutations that dissect TPP1’s functions. Our results extend upon current structural data to reveal that the TPP1-TIN2 interface is more extensive than previously thought, and highlight the robustness of the POT1-TPP1 interface. Introduction of separation-of-function mutants alongside known TPP1 telomeropathy mutations in mouse hematopoietic stem cells (mHSCs) lacking endogenous TPP1 demonstrated a clear phenotypic demarcation. TIN2- and POT1-binding mutants were unable to rescue mHSC failure resulting from end-deprotection. In contrast, TPP1 telomeropathy mutations sustained mHSC viability, consistent with them selectively impacting end-replication. These results highlight the power of scanning mutagenesis in revealing structural interfaces and dissecting multifunctional genes.

Authors

Sherilyn Grill, Shilpa Padmanaban, Ann Friedman, Eric Perkey, Frederick Allen, Valerie M. Tesmer, Jennifer Chase, Rami Khoriaty, Catherine E. Keegan, Ivan Maillard, Jayakrishnan Nandakumar

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An inducible Cre mouse for studying roles of the RPE in retinal physiology and disease
Elliot H. Choi, … , Krzysztof Palczewski, Philip D. Kiser
Elliot H. Choi, … , Krzysztof Palczewski, Philip D. Kiser
Published March 30, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.146604.
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An inducible Cre mouse for studying roles of the RPE in retinal physiology and disease

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Abstract

The retinal pigment epithelium (RPE) provides vital metabolic support for retinal photoreceptor cells and also is an important player in numerous retinal diseases. Gene manipulation in mice using the Cre-LoxP system is an invaluable tool for studying the genetic basis of these retinal diseases. However, existing RPE-targeted Cre mouse lines have critical limitations that restrict their reliability for studies of disease pathogenesis and treatment, including mosaic Cre expression, inducer-independent activity, off-target Cre expression, and intrinsic toxicity. Here, we report the generation and characterization of a knock-in mouse line in which a P2A-CreERT2 coding sequence is fused with the native RPE-specific 65 kDa protein (Rpe65) gene for co-translational expression of CreERT2. Cre+/- mice were able to recombine a stringent Cre reporter allele with >99% efficiency and absolute RPE specificity upon tamoxifen induction at both post-natal days (PD) 21 and 50. Tamoxifen-independent Cre activity was negligible at PD64. Moreover, tamoxifen-treated Cre+/- mice displayed no signs of structural or functional retinal pathology up to 4 months of age. Despite weak RPE65 expression from the knock-in allele, visual cycle function was normal in Cre+/- mice. These data indicate that Rpe65CreERT2 mice are well-suited for studies of gene function and pathophysiology in the RPE.

Authors

Elliot H. Choi, Susie Suh, David E. Einstein, Henri Leinonen, Zhiqian Dong, Sriganesh Ramachandra Rao, Steven J. Fliesler, Seth Blackshaw, Minzhong Yu, Neal S. Peachey, Krzysztof Palczewski, Philip D. Kiser

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Chromosome 8 gain is associated with high-grade transformation in MPNST
Carina A. Dehner, … , Jack F. Shern, Angela C. Hirbe
Carina A. Dehner, … , Jack F. Shern, Angela C. Hirbe
Published February 16, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.146351.
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Chromosome 8 gain is associated with high-grade transformation in MPNST

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Abstract

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma which commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven success in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared to the primary tumors from which they were derived using copy number analysis, whole-exome and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft tissue sarcomas. Taken together, these data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis, and may account for the aggressive nature and poor outcomes in this sarcoma subtype.

Authors

Carina A. Dehner, Chang In Moon, Xiyuan Zhang, Zhaohe Zhou, Christopher A. Miller, Hua Xu, Xiaodan Wan, Kuangying Yang, R. Jay Mashl, Sara J.C. Gosline, Yuxi Wang, Xiaochun Zhang, Abigail Godec, Paul A. Jones, Sonika Dahiya, Himanshi Bhatia, Tina Primeau, Shunqiang Li, Kai Pollard, Fausto J. Rodriguez, Li Ding, Christine A. Pratilas, Jack F. Shern, Angela C. Hirbe

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Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy
Xiaoying Zhou, … , Vanitha Sampath, Kari C. Nadeau
Xiaoying Zhou, … , Vanitha Sampath, Kari C. Nadeau
Published February 11, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.143058.
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Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy

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Abstract

DNA methylation (DNAm) has been shown to play a role in mediating food allergy, however, the mechanism by which it does so is poorly understood. In this study, we used targeted NextGen bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) vs non-allergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity) as well as DNAm signature combinations with superior diagnostic potential compared to serum peanut specific-IgE for PA vs. NA. Further, we found that following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared to NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than that in randomly paired genetically unrelated individuals, suggesting that PA related DNAm signatures may be associated with genetic factors.

Authors

Xiaoying Zhou, Xiaorui Han, Shu-Chen Lyu, Bryan J. Bunning, Laurie Kost, Iris Chang, Shu Cao, Vanitha Sampath, Kari C. Nadeau

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