Loss-of-function myeloperoxidase mutations are associated with increased neutrophil counts and pustular skin disease

AbstractThe identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole exome sequencing of 19 unrelated cases, we identified one affected individual harbouring a homozygous splice-site mutation (c.2031-2A>C) in MPO. The same homozygous change was subsequently identified in a further subject suffering from acral pustular psoriasis, a disease phenotypically related to GPP.MPO encodes myeloperoxidase, an essential component of neutrophil azurophil granules. Of interest, the c.2031-2A>C allele was previously described as a genetic determinant of myeloperoxidase deficiency (MPOD), a condition which can causes recurrent infections. Here, a systematic literature review identified four individuals suffering from MPOD and pustular skin disease, further strengthening the link between MPO and pustular inflammation.A subsequent analysis of the UK Biobank cohort demonstrated that the c.2031-2A>C allele was associated with increased neutrophil abundance in the general population (P=5.1×10−6). The same applied to three further MPOD mutations for which genotype data was available, with two alleles generating p-values <10−10. Finally, treatment of healthy neutrophils with an MPO inhibitor reduced cell apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers.These findings identify MPO mutations as genetic determinants of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

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Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

International Journal of Molecular Sciences ◽

10.3390/ijms22073786 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3786

Author(s):

Andreas Brodehl ◽

Alexey Meshkov ◽

Roman Myasnikov ◽

Anna Kiseleva ◽

Olga Kulikova ◽

...

Keyword(s):

Medical History ◽

Splice Site Mutation ◽

Pathogenic Mutation ◽

Large Deletion ◽

Loss Of Function ◽

Arrhythmogenic Cardiomyopathy ◽

Site Mutation ◽

Snp Arrays ◽

Number Of Patients ◽

History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

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Identification of a Novel EXT Mutation in A Kindred With Hereditary Multiple Exostoses Using Whole-Exome Sequencing and Overview of Mutation Spectrum

10.21203/rs.3.rs-770260/v1 ◽

2021 ◽

Author(s):

yanhan deng ◽

yujian liu ◽

wei tu ◽

liu yang

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutation Spectrum ◽

Loss Of Function ◽

Site Mutation ◽

Hereditary Multiple Exostoses ◽

Multiple Osteochondromas ◽

Online Databases ◽

Whole Exome ◽

Multiple Exostoses

Abstract Background: Hereditary Multiple Osteochondromas(HMO) is a rare genetic musculoskeletal disorder characterized by multiple osteochondromas that form near to the growth plates of many bones. Loss-of-function mutations in EXT1 or EXT2 that encode glycosyltrasferases are the causal mutations for most HMO patients.Methods: After collecting the family history and clinical information, we used Whole-Exome Sequencing to find the pathogenic mutations in one Chinese Hereditary Multiple Exostoses pedigree. Sanger sequencing and relevant online databases were used to validate the screened variants. Lollipop plots were drew to map the reported mutations from online databases (Multiple Osteochondroma Mutation Database and clinvar)on a linear protein domains by MutationMapper.Results: A novel heterozygous splicing-site mutation in gene EXT1 (NM_000127:exon5:c.1417+1G>C，chr8:118834703) was found in this pedigree and mutation spectrum of genes EXT1 and EXT2 were demonstrated.Conclusions: Our results help this pedigree to identify the pathogenic variant and guide the prenatal diagnosis, also expand the mutation spectrum in Hereditary Multiple Osteochondromas.

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Striking Cardiac Phenotypic Variability in A Chinese Family With A MYH7 Splice Site Mutation

10.21203/rs.3.rs-273275/v1 ◽

2021 ◽

Author(s):

Peng Tu ◽

Hairui Sun ◽

Xiaohang Zhang ◽

Qian Ran ◽

suzhen Ran ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Splice Site ◽

Phenotypic Variability ◽

Splice Site Mutation ◽

Left Ventricular ◽

Chinese Family ◽

Site Mutation ◽

Cardiac Phenotype ◽

Whole Exome

Abstract Background: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare congenital heart defect (CHD), genetics defects have been found in patients with LVNC and their family members; and MYH7 is the most common genetic associated with LVNC. Methods: A trio (fetus and the parents) whole-exome sequencing (WES) was performed when the fetus was found with Ebstein's anomaly (EA), heart dilatation, perimembranous ventricular septal defects (VSD), mild seroperitoneum and single umbilical artery (SUA).Results: Whole-exome sequencing identified a maternal inherited heterozygous splice site mutation in MYH7 (NM_000257.3:c.732+1G>A). Subsequent Sanger sequencing confirmed that the mutation was heterozygous in the fetus, the old sister, the grandmother, and the mother. QPCR experiment using RNA from blood lymphocytes but were unable to amplify any product.Conclusion: This familial case underlines that the striking cardiac phenotypic of MYH7 mutation (the c.732+1G>A spice site variant) may be highly variable. The mechanistic studies which could uncover candidate genes modulating cardiac phenotype associated with LVNC/EA should be proceed.

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Dermatology

Oxford Assess and Progress: Clinical Specialties ◽

10.1093/oso/9780198802907.003.0019 ◽

2018 ◽

Author(s):

Gemma Simcox

Keyword(s):

Quality Of Life ◽

Skin Disease ◽

Skin Diseases ◽

Systemic Disease ◽

Management Plan ◽

Dermatological Examination ◽

Common Skin ◽

Life Threatening ◽

The Uk

Skin disease has a serious impact on an individual’s quality of life. It is well recognized that conditions such as psoriasis may have a similar impact on a patient’s quality of life to chronic diseases such as diabetes, hypertension, and depression. Skin problems account for approximately 20% of all patient consultations in primary care in the UK. It is important that clinicians are able to diagnose common skin diseases such as acne, eczema, psoriasis, and cutaneous malignancies and initiate an appropriate management plan. This requires the ability to take a full history and conduct a complete examination. A complete dermatological examination involves examination of the entire skin, mucous membranes, hair, and nails. The description of cutaneous pathologies should include the location and distribution of lesions. The morphology of a lesion or each component of a generalized eruption should be noted. Other organ systems may also need to be examined. The questions in this chapter will test your knowledge of the skin problems that are frequently encountered in non-specialist clinical practice. Other more rare skin disorders are also covered, either because they are potentially life-threatening or because they are a sign of systemic disease. The questions are designed to improve your ability to recognize the morphology and distribution of cutaneous physical signs. Hopefully you will find these questions stimulating and an aid to improving your knowledge of skin disease.

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ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Nature Communications ◽

10.1038/s41467-019-12428-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Marie F. Smeland ◽

Conor McClenaghan ◽

Helen I. Roessler ◽

Sanne Savelberg ◽

Geir Åsmund Myge Hansen ◽

...

Keyword(s):

Intellectual Disability ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Splice Site Mutation ◽

Cerebral White Matter ◽

Sulfonylurea Receptor ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Site Mutation ◽

Gain Of Function

Abstract Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

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Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei

10.21203/rs.2.15420/v1 ◽

2019 ◽

Author(s):

Mei Sim Lung ◽

Catherine A. Mitchell ◽

Maria A. Doyle ◽

Andrew C. Lynch ◽

Kylie L. Gorringe ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Splice Site ◽

Pseudomyxoma Peritonei ◽

Loss Of Function ◽

Site Mutation ◽

Germline Variants ◽

Missense Variants ◽

Whole Exome ◽

Mucinous Tumours

Abstract Background Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. Materials and Methods Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH. Results Seventeen novel variants in 17 genes were shared by the father and daughter: a nonsense mutation in REEP5 , an essential splice site mutation in THOP1 , and 15 missense variants. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes ( EXOG , RANBP2, RANBP6 and TNFRSF1B ) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic PMP; no LoF or rare missense germline variants were identified. Conclusion Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.

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TALPID3 controls centrosome and cell polarity and the human ortholog KIAA0586 is mutated in Joubert syndrome (JBTS23)

eLife ◽

10.7554/elife.08077 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 32

Author(s):

Louise A Stephen ◽

Hasan Tawamie ◽

Gemma M Davis ◽

Lars Tebbe ◽

Peter Nürnberg ◽

...

Keyword(s):

Cell Polarity ◽

Protein Localization ◽

Splice Site Mutation ◽

Joubert Syndrome ◽

Homozygosity Mapping ◽

Model Organisms ◽

Site Mutation ◽

Whole Exome ◽

Organ Systems ◽

Human Ortholog

Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects.

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A Novel Splice Site Variant in FOXN1 in A Patient with Abnormal Newborn Screening for Severe Combined Immunodeficiency and Congenital Lymphopenia

LymphoSign Journal ◽

10.14785/lymphosign-2021-0013 ◽

2021 ◽

Author(s):

Ori Scott ◽

Jenny Garkaby ◽

Jessica Willett-Pachul ◽

Yehonatan Pasternak

Keyword(s):

Splice Site ◽

Severe Combined Immunodeficiency ◽

Splice Site Mutation ◽

Missense Mutations ◽

Combined Immunodeficiency ◽

Site Mutation ◽

Cd8 Cells ◽

Cell Counts ◽

Epithelial Development ◽

Whole Exome

Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations. Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency. Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation. Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother. Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.

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Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106379 ◽

2019 ◽

Vol 57 (3) ◽

pp. 187-194 ◽

Cited By ~ 2

Author(s):

Wenjing Wang ◽

Jie Dong ◽

Biaobang Chen ◽

Jing Du ◽

Yanping Kuang ◽

...

Keyword(s):

Missense Mutation ◽

Splice Site ◽

Genetic Factors ◽

Splice Site Mutation ◽

Female Infertility ◽

Site Mutation ◽

Whole Exome ◽

Pronuclear Formation ◽

Embryonic Arrest

BackgroundAbnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in female infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in female infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown.ObjectiveWe aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest.MethodsWhole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay.ResultsWe identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation.ConclusionsOur study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human female meiosis and fertility.

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