scholarly journals Novel genetic variant of HPS1 gene in Hermansky-Pudlak syndrome with fulminant progression of pulmonary fibrosis: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Martina Doubková ◽  
Jakub Trizuljak ◽  
Zuzana Vrzalová ◽  
Anna Hrazdirová ◽  
Ivona Blaháková ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Clinical Manifestation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Oculocutaneous Albinism ◽  
Differential Diagnostics ◽  
Compound Heterozygous ◽  
Carrier Status ◽  
Whole Exome ◽  
Hermansky Pudlak Syndrome

Abstract Background Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diathesis, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes. Homozygous or compound heterozygous pathological variants in HPS1, HPS3, HPS4, and several other genes lead to clinical manifestation of the disease. Case presentation A 57-year-old female was admitted with congenital oculocutaneous albinism, thrombocytopathy and late-onset accelerated pulmonary fibrosis (first symptoms from age 50 onwards). Chest high-resolution computed tomography identified thickening of peribronchovascular interstitium, bronchiectasis, reticulations, honeycombing, ground glass opacities and lung parenchyma consolidations. HPS was clinically suspected. We performed whole exome sequencing (WES), a form of massive parallel sequencing, of proband-parents trio. Whole exome libraries were processed using KAPA Hyper Prep Kit, SeqCap EZ MedExome Enrichment Kit and HyperCap Bead Kit according to the SeqCap EZ HyperCap Workflow. The paired-end 2 × 75 bp sequencing was performed on the Illumina NextSeq 500 Sequencer (Illumina Inc., USA). Furthermore, obtained variants by WES were evaluated using a virtual panel of genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and PLDN. We identified a compound heterozygous genotype in HPS1 gene in the proband. We identified a pathogenic frameshift variant c.1189delC; p.(Gln397Serfs*2), resulting in a premature stop codon. This variant has been previously associated with HPS. Furthermore, we characterized previously undescribed nonsense variant c.1507C > T; p.(Gln503*), resulting in a premature stop codon and mRNA degradation through nonsense-mediated decay. Sanger sequencing validated the presence of both variants and simultaneously confirmed the heterozygous carrier status of parents. Unfortunately, the patient died due to fulminant progression of pulmonary fibrosis 2 months after diagnostics. Conclusions Compound heterozygous mutations in HPS1 in the proband lead to disruption of HPS1 gene and clinical manifestation of HPS with severe pulmonary fibrosis. This case illustrates the need to consider HPS in differential diagnostics of pulmonary fibrosis. Pulmonary fibrosis is a common cause of death in HPS patients. Earlier diagnosis may enable better treatment for these patients.

scholarly journals Hermansky-Pudlak Syndrome and Lung Disease: Pathogenesis and Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Pamela Velázquez-Díaz ◽  
Erika Nakajima ◽  
Parand Sorkhdini ◽  
Ashley Hernandez-Gutierrez ◽  
Adam Eberle ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Molecular Mechanisms ◽  
Management Strategies ◽  
Oculocutaneous Albinism ◽  
Alveolar Epithelial Cells ◽  
Multisystem Disorder ◽  
Alveolar Epithelial ◽  
Novel Treatments ◽  
Molecular Approaches ◽  
Hermansky Pudlak Syndrome

Hermansky-Pudlak Syndrome (HPS) is a rare, genetic, multisystem disorder characterized by oculocutaneous albinism (OCA), bleeding diathesis, immunodeficiency, granulomatous colitis, and pulmonary fibrosis. HPS pulmonary fibrosis (HPS-PF) occurs in 100% of patients with subtype HPS-1 and has a similar presentation to idiopathic pulmonary fibrosis. Upon onset, individuals with HPS-PF have approximately 3 years before experiencing signs of respiratory failure and eventual death. This review aims to summarize current research on HPS along with its associated pulmonary fibrosis and its implications for the development of novel treatments. We will discuss the genetic basis of the disease, its epidemiology, and current therapeutic and clinical management strategies. We continue to review the cellular processes leading to the development of HPS-PF in alveolar epithelial cells, lymphocytes, mast cells, and fibrocytes, along with the molecular mechanisms that contribute to its pathogenesis and may be targeted in the treatment of HPS-PF. Finally, we will discuss emerging new cellular and molecular approaches for studying HPS, including lentiviral-mediated gene transfer, induced pluripotent stem cells (iPSCs), organoid and 3D-modelling, and CRISPR/Cas9-based gene editing approaches.

scholarly journals Attenuated Type of Asphyxiating Thoracic Dysplasia due to Mutations in DYNC2H1 Gene

2019 ◽  
Vol 120 (4) ◽  
pp. 124-130
Author(s):  
Anna Čechová ◽  
Alice Baxová ◽  
Jiří Zeman ◽  
Lukáš Lambert ◽  
Tomáš Honzík ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Chest Circumference ◽  
Anthropometric Parameters ◽  
Age Related ◽  
Whole Exome ◽  
Asphyxiating Thoracic Dysplasia ◽  
Health And Disease ◽  
Postnatal Adaptation

Asphyxiating thoracic dysplasia (ATD) represents a heterogeneous group of skeletal dysplasias with short ribs, narrow chest and reduced thoracic capacity. Mutations in several genes including IFT80, DYNC2H1, TTC21B and WDR19 have been found in patients with ATD. Both severe and milder course of the disease were described in correlation with secondary involvement of lung’s function. Two children with attenuated form of ATD are described. Their anthropometric parameters for birth weight, length and head circumference were normal but narrow thorax was observed in both of them in early infancy with chest circumference < –3 SD (standard deviation) in comparison to age related controls. The postnatal adaptation and development of both children was uneventful except for mild tachypnoea in one of them which persisted till the age of 6 months. In both children, radiographs revealed narrow upper half of the chest with shorter ribs and atypical configuration of pelvis with horizontally running acetabula and coarse internal edges typical for ATD. Molecular analyses using whole exome sequencing in one family revealed that the patient is compound heterozygote in DYNC2H1 gene for a frame-shift mutation c.4458delT resulting in premature stop-codon p.Phe1486Leufs*11 and a missense mutation c.9044A>G (p.Asp3015Gly). The second family refused the DNA analysis. Regular monitoring of anthropometric parameters during childhood is of big importance both in health and disease. In addition, measurement of the chest circumference should be included, at least at birth and during infancy.

scholarly journals AIMP1 Mutation Long-Term Follow-Up, With Decreased Brain N-Acetylaspartic Acid and Secondary Mitochondrial Abnormalities

2019 ◽  
Vol 6 ◽  
pp. 2329048X1982952 ◽  
Author(s):  
Aneal Khan ◽  
Jennifer Bennett ◽  
Morris H. Scantlebury ◽  
Xing-Chang Wei ◽  
Marina Kerr
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Monozygotic Twins ◽  
Trna Synthetase ◽  
Resonance Spectroscopy ◽  
Multifunctional Protein ◽  
Whole Exome ◽  
Long Term Follow Up

Aminoacyl transfer RNA (tRNA) synthetase complex-interacting multifunctional protein I is a noncatalytic component of tRNA multi-synthetase complexes. Although important in joining tRNAs to their cognate amino acids, AIMP1 has several other functions including axonal growth, cytokine activity, and interactions with N-acetylaspartic acid in ribosomal tRNA synthetase complexes. Further, N-acetylaspartic acid donates an aspartate during myelination and is therefore important to axonal integrity. Mutations in AIMP1 can disrupt these functions, as demonstrated in this clinical case study of 2 monozygotic twins, who display congenital opisthotonus, microcephaly, severe developmental delay, and seizures. Whole exome sequencing was used to identify a premature stop codon in the AIMP1 gene (g. 107248613_c.115C>T; p.(Gln39). In the absence of whole exome sequencing, we propose that decreased N-acetylaspartic acid peaks on magnetic resonance spectroscopy could act as a biomarker for AIMP1 mutations.

Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3181-3189 ◽  
Author(s):  
Babette Gwynn ◽  
Jose A. Martina ◽  
Juan S. Bonifacino ◽  
Elena V. Sviderskaya ◽  
M. Lynn Lamoreux ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Trafficking ◽  
Protein Complexes ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Amino Acid Identity ◽  
Organelle Biogenesis ◽  
Hermansky Pudlak Syndrome ◽  
Human Orthologue ◽  
Lysosome Related Organelles

Abstract Hermansky-Pudlak syndrome (HPS), a disorder of organelle biogenesis, affects lysosomes, melanosomes, and platelet dense bodies. Seven genes cause HPS in humans (HPS1-HPS7) and at least 15 nonallelic mutations cause HPS in mice. Where their function is known, the HPS proteins participate in protein trafficking and vesicle docking/fusion events during organelle biogenesis. HPS-associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; biogenesis of lysosome-related organelles complex 1 (BLOC-1), consisting of 4 HPS proteins (pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. Here, we report the cloning of the mouse HPS mutation reduced pigmentation (rp). We show that the wild-type rp gene encodes a novel, widely expressed 195-amino acid protein that shares 87% amino acid identity with its human orthologue and localizes to punctate cytoplasmic structures. Further, we show that phosphorylated RP is part of the BLOC-1 complex. In mutant rp/rp mice, a premature stop codon truncates the protein after 79 amino acids. Defects in all the 5 known components of BLOC-1, including RP, cause severe HPS in mice, suggesting that the subunits are nonredundant and that BLOC-1 plays a key role in organelle biogenesis.

A rare diagnosis: Hermansky-Pudlak syndrome in a patient with pulmonary fibrosis, oculocutaneous albinism and thrombocytopathy

2019 ◽  
Author(s):  
Martina Doubková ◽  
Jakub Trizuljak ◽  
Anna Hrazdirová ◽  
Zuzana Vrzalová ◽  
Ivona Blaháková ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Oculocutaneous Albinism ◽  
Hermansky Pudlak Syndrome ◽  
Rare Diagnosis

scholarly journals Hermansky–Pudlak syndrome pulmonary fibrosis: a rare inherited interstitial lung disease

2021 ◽  
Vol 30 (159) ◽  
pp. 200193
Author(s):  
Tadafumi Yokoyama ◽  
Bernadette R. Gochuico
Keyword(s):  
Interstitial Lung Disease ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Genetic Diseases ◽  
Autosomal Recessive Disorder ◽  
Oculocutaneous Albinism ◽  
Excessive Bleeding ◽  
Lung Physiology ◽  
Hermansky Pudlak Syndrome ◽  
Fibrotic Lung Disease

Pulmonary fibrosis is a progressive interstitial lung disease of unknown aetiology with a poor prognosis. Studying genetic diseases associated with pulmonary fibrosis provides insights into the pathogenesis of the disease. Hermansky–Pudlak syndrome (HPS), a rare autosomal recessive disorder characterised by abnormal biogenesis of lysosome-related organelles, manifests with oculocutaneous albinism and excessive bleeding of variable severity. Pulmonary fibrosis is highly prevalent in three out of 10 genetic types of HPS (HPS-1, HPS-2 and HPS-4). Thus, genotyping of individuals with HPS is clinically relevant. HPS-1 tends to affect Puerto Rican individuals due to a genetic founder effect. HPS pulmonary fibrosis shares some clinical features with idiopathic pulmonary fibrosis (IPF), including dyspnoea, cough, restrictive lung physiology and computed tomography (CT) findings of fibrosis. In contrast to IPF, HPS pulmonary fibrosis generally affects children (HPS-2) or middle-aged adults (HPS-1 or HPS-4) and may be associated with ground-glass opacification in CT scans. Histopathology of HPS pulmonary fibrosis, and not IPF, shows vacuolated hyperplastic type II cells with enlarged lamellar bodies and alveolar macrophages with lipofuscin-like deposits. Antifibrotic drugs approved as treatment for IPF are not approved for HPS pulmonary fibrosis. However, lung transplantation has been performed in patients with severe HPS pulmonary fibrosis. HPS pulmonary fibrosis serves as a model for studying fibrotic lung disease and fibrosis in general.

scholarly journals Analbuminemia Produced by a Novel Splicing Mutation

2007 ◽  
Vol 53 (8) ◽  
pp. 1549-1552 ◽  
Author(s):  
Lorenzo Dolcini ◽  
Gianluca Caridi ◽  
Monica Dagnino ◽  
Alberto Sala ◽  
Selim Gökçe ◽  
...  
Keyword(s):  
Stop Codon ◽  
Direct Sequencing ◽  
Consensus Sequence ◽  
Premature Stop Codon ◽  
Autosomal Recessive Disorder ◽  
Single Strand Conformation Polymorphism ◽  
Heteroduplex Analysis ◽  
Compound Heterozygous ◽  
Albumin Concentration ◽  
Albumin Gene

Abstract Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating human serum albumin in homozygous or compound heterozygous individuals. It is an allelic heterogeneous defect, caused by a variety of mutations within the albumin gene. The analbuminemic condition was diagnosed in a Turkish female infant on the basis of low albumin concentration (∼9.0 g/L). The albumin gene was screened by single-strand conformation polymorphism and heteroduplex analysis and submitted to direct sequencing. The proband was found to be homozygous for a T→C transition at nucleotide 13381, the 2nd base of intron 11. The effect of this previously unreported mutation, which inactivates the strongly conserved GT dinucleotide at the 5′ splice site consensus sequence of intron 11, was evaluated by examining the cDNA obtained by reverse transcription-PCR from the albumin mRNA extracted from the proband leukocytes. This analysis revealed that the mutation, named Bartin for the geographical origin of the patient’s family, results in the skipping of exon 11. The subsequent frameshift within exon 12 originates a premature stop codon located 5 codons downstream at position 411. The predicted translation product would consist of 410 amino acids. This novel extensive cDNA alteration is responsible for the analbuminemic trait.

scholarly journals Aberrant Splicing of SDHC in Families With Unexplained Succinate Dehydrogenase-Deficient Paragangliomas

2020 ◽  
Vol 4 (12) ◽  
Author(s):  
Sunita M C De Sousa ◽  
John Toubia ◽  
Tristan S E Hardy ◽  
Jinghua Feng ◽  
Paul Wang ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Transcriptome Analysis ◽  
Haplotype Analysis ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Chromosome 1 ◽  
Sequencing Analysis ◽  
Kit Mutation ◽  
Whole Exome ◽  
Genetic Test Results

Abstract Context Germline mutations in the succinate dehydrogenase genes (SDHA/B/C/D, SDHAF2—collectively, “SDHx”) have been implicated in paraganglioma (PGL), renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pituitary adenoma (PA). Negative SDHB tumor staining is indicative of SDH-deficient tumors, usually reflecting an underlying germline SDHx mutation. However, approximately 20% of individuals with SDH-deficient tumors lack an identifiable germline SDHx mutation. Methods We performed whole-exome sequencing (WES) of germline and tumor DNA followed by Sanger sequencing validation, transcriptome analysis, metabolomic studies, and haplotype analysis in 2 Italian-Australian families with SDH-deficient PGLs and various neoplasms, including RCC, GIST, and PA. Results Germline WES revealed a novel SDHC intronic variant, which had been missed during previous routine testing, in 4 affected siblings of the index family. Transcriptome analysis demonstrated aberrant SDHC splicing, with the retained intronic segment introducing a premature stop codon. WES of available tumors in this family showed chromosome 1 deletion with loss of wild-type SDHC in a PGL and a somatic gain-of-function KIT mutation in a GIST. The SDHC intronic variant identified was subsequently detected in the second family, with haplotype analysis indicating a founder effect. Conclusions This is the deepest intronic variant to be reported among the SDHx genes. Intronic variants beyond the limits of standard gene sequencing analysis should be considered in patients with SDH-deficient tumors but negative genetic test results.

Late onset and pregnancy-induced congenital thrombotic thrombocytopenic purpura

2014 ◽  
Vol 34 (03) ◽  
pp. 244-248 ◽  
Author(s):  
J. A. Hovinga ◽  
K. Lackner ◽  
H.-G. Füllemann ◽  
B. Lämmle ◽  
I. Scharrer ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Late Onset ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Compound Heterozygous ◽  
Thrombocytopenic Purpura ◽  
Exon 2 ◽  
Acid Therapy ◽  
Gestational Week ◽  
Adamts13 Deficiency

SummaryWe report on our patient (case 2) who experienced a first acute episode of thrombotic thrombocytopenic purpura (TTP) at the age of 19 years during her first pregnancy in 1976 which ended in a spontaneous abortion in the 30th gestational week. Treatment with red blood cell concentrates was implemented and splenectomy was performed. After having suffered from several TTP episodes in 1977, possibly mitigated by acetylsalicylic acid therapy, an interruption and sterilization were performed in 1980 in her second pregnancy thereby avoiding another disease flare-up. Her elder sister (case 1) had been diagnosed with TTP in 1974, also during her first pregnancy. She died in 1977 during her second pregnancy from a second acute TTP episode. Diagnosis: In 2013 a severe ADAMTS13 deficiency of <10% without detectable ADAMTS13 inhibitor was repeatedly found. Investigation of the ADAMTS13 gene showed that the severe ADAMTS13 deficiency was caused by compound heterozygous ADAMTS13 mutations: a premature stop codon in exon 2 (p.Q44X), and a missense mutation in exon 24 (p.R1060W) associated with low but measurable ADAMTS13 activity. Conclusion: Genetic analysis of the ADAMTS13 gene is important in TTP patients of all ages if an ADAMTS13 inhibitor has been excluded.

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