Genetic variants associated with Hermansky-Pudlak syndrome

Merideth, Melissa A.; Introne, Wendy J.; Wang, Jennifer A.; O’Brien, Kevin; Huizing, Marjan; Gochuico, Bernadette R.

doi:10.1080/09537104.2019.1663810

Cited by 18 publications

(10 citation statements)

References 23 publications

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“…Its molecular basis is heterogenous, with mutations in up to 11 different genes ( Table 3 ), all of which participate directly or indirectly in intracellular vesicular traffic. A relation between the affected gene and clinical severity has been proven (particularly in HPS subtypes 1 and 4), making early molecular diagnosis particularly important [ 102 , 103 , 104 ].…”

Section: Inherited Platelet Disorders Of Particular Clinical Relevancementioning

confidence: 99%

Inherited Platelet Disorders: An Updated Overview

Palma-Barqueros

Revilla

Sánchez

et al. 2021

IJMS

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Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype–phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory.

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Section: Inherited Platelet Disorders Of Particular Clinical Relevancementioning

confidence: 99%

Inherited Platelet Disorders: An Updated Overview

Palma-Barqueros

Revilla

Sánchez

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…The complex of TF and activated factor VII serves to activate other coagulation factors including F9 (Millar et al, 2000 ). Furthermore, the BLOC1 complex is also known to regulate coagulation (Merideth et al, 2020 ), and its members BLOC1S1, BLOC1S2, BLOC1S3 , ( Starcevic & Dell'Angelica, 2004 ) and DTNBP3 (Nazarian et al, 2006 ) are part of our newly discovered list of proteins in human milk that are associated with calcium metabolism.…”

Section: Discussionmentioning

confidence: 99%

Quantification of FAM20A in human milk and identification of calcium metabolism proteins

Patel

Klootwijk

Whiting

et al. 2021

Physiological Reports

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Background FAM20A, a recently discovered protein, is thought to have a fundamental role in inhibiting ectopic calcification. Several studies have demonstrated that variants of FAM20A are causative for the rare autosomal recessive disorder, enamel‐renal syndrome (ERS). ERS is characterized by defective mineralization of dental enamel and nephrocalcinosis suggesting that FAM20A is an extracellular matrix protein, dysfunction of which causes calcification of the secretory epithelial tissues. FAM20A is a low‐abundant protein that is difficult to detect in biofluids such as blood, saliva, and urine. Thus, we speculated the abundance of FAM20A to be high in human milk, since the secretory epithelium of lactating mammary tissue is involved in the secretion of highly concentrated calcium. Therefore, the primary aim of this research is to describe the processes/methodology taken to quantify FAM20A in human milk and identify other proteins involved in calcium metabolism. Method This study used mass spectrometry‐driven quantitative proteomics: (1) to quantify FAM20A in human milk of three women and (2) to identify proteins associated with calcium regulation by bioinformatic analyses on whole and milk fat globule membrane fractions. Results Shotgun MS/MS driven proteomics identified FAM20A in whole milk, and subsequent analysis using targeted proteomics also successfully quantified FAM20A in all samples. Combination of sample preparation, fractionation, and LC‐MS/MS proteomics analysis generated 136 proteins previously undiscovered in human milk; 21 of these appear to be associated with calcium metabolism. Conclusion Using mass spectrometry‐driven proteomics, we successfully quantified FAM20A from transitional to mature milk and obtained a list of proteins involved in calcium metabolism. Furthermore, we show the value of using a combination of both shotgun and targeted driven proteomics for the identification of this low abundant protein in human milk.

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“…Platelet dense bodies contain calcium, polyphosphates, serotonin (5-HT), adenosine triphosphate (ATP), and adenosine diphosphate (ADP). Since dense granules release their contents when stimulated and ADP can further induce aggregation of other platelets, defects in platelet dense bodies will cause storage pool deficiency and therefore coagulation dysfunction [ 26 ]. In our study, the patient presented with bleeding diathesis since his childhood, and it became less severe over time.…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Identified a Novel Homozygous Frameshift Mutation of HPS3 in a Consanguineous Family with Hermansky-Pudlak Syndrome

Wang

Liu

Dong

et al. 2021

BioMed Research International

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Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder with an autosomal recessive inherited pattern. It is mainly characterized by deficiencies in lysosome-related organelles, such as melanosomes and platelet-dense granules, and leads to albinism, visual impairment, nystagmus, and bleeding diathesis. A small number of patients will present with granulomatous colitis or fatal pulmonary fibrosis. At present, mutations in ten known genetic loci (HPS1–11) have been identified to be the genetic cause of HPS. In this study, we enrolled a consanguineous family who presented with typical HPS phenotypes, such as albinism, visual impairment, nystagmus, and bleeding diathesis. Whole-exome sequencing and Sanger sequencing were applied to explore the genetic lesions of the patient. A novel homozygous frameshift mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 was identified and cosegregated in the family members. Furthermore, real-time PCR confirmed that the mutation decreased the expression of HPS3, which has been identified as the disease-causing gene of HPS type 3. According to ACMG guidelines, the novel mutation, resulting in a premature stop codon at amino acid 442, is a pathogenic variant. In summary, we identified a novel mutation (NM_032383.5, c.1231dupG/p.Aps411GlyfsTer32) of HPS3 in a family with HPS. Our study expanded the variant spectrum of the HPS3 gene and contributed to genetic counseling and prenatal genetic diagnosis of the family.

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Genetic variants associated with Hermansky-Pudlak syndrome

Cited by 18 publications

References 23 publications

Inherited Platelet Disorders: An Updated Overview

Inherited Platelet Disorders: An Updated Overview

Quantification of FAM20A in human milk and identification of calcium metabolism proteins

Whole-Exome Sequencing Identified a Novel Homozygous Frameshift Mutation of HPS3 in a Consanguineous Family with Hermansky-Pudlak Syndrome

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