Key Points• CLEC4M plays a role in the clearance of VWF.• CLEC4M polymorphisms contribute to the genetic variability of VWF plasma levels.Genetic variation in or near the C-type lectin domain family 4 member M (CLEC4M) has been associated with plasma levels of von Willebrand factor (VWF) in healthy individuals. CLEC4M is a lectin receptor with a polymorphic extracellular neck region possessing a variable number of tandem repeats (VNTR). A total of 491 participants (318 patients with type 1 von Willebrand disease [VWD] and 173 unaffected family members) were genotyped for the CLEC4M VNTR polymorphism. Family-based association analysis on kindreds with type 1 VWD demonstrated an excess transmission of VNTR 6 to unaffected individuals (P 5 .0096) and an association of this allele with increased VWF:RCo (P 5 .029). CLEC4M-Fc bound to VWF. Immunofluorescence and enzyme-linked immunosorbent assay demonstrated that HEK 293 cells transfected with CLEC4M bound and internalized VWF. Cells expressing 4 or 9 copies of the CLEC4M neck region VNTR showed reduced interaction with VWF relative to CLEC4M with 7 VNTR (CLEC4M 4%-60% reduction, P < .001; CLEC4M 9%-45% reduction, P 5 .006). Mice expressing CLEC4M after hydrodynamic liver transfer have a 46% decrease in plasma levels of VWF (P 5 .0094). CLEC4M binds to and internalizes VWF, and polymorphisms in the CLEC4M gene contribute to variable plasma levels of VWF. (Blood. 2013;121(26):5228-5237) Introduction von Willebrand factor (VWF) is a plasma glycoprotein that mediates platelet adhesion and aggregation and acts as the carrier protein for factor VIII (FVIII). VWF synthesis by endothelial cells 1 and megakaryocytes 2 involves complex post-translational modifications including dimerization, glycosylation, sulfation, multimerization, and propeptide cleavage (reviewed by Sadler 3 ). The protein is either constitutively secreted into the plasma and subendothelium or is stored in endothelial Weibel-Palade bodies or platelet a granules from which release can be mediated by a number of chemical and biomechanical stimuli.Plasma VWF levels in healthy participants show a fourfold range (0.50-2.00 IU/mL). 4 These levels are influenced by a variety of genetic and acquired factors. ABO blood group contributes approximately 30% of the genetic influence, 5,6 whereas age, 6,7 acute-phase stimuli, [8][9][10] and several endocrine abnormalities represent acquired determinants of VWF levels. 7,11 In type 1 von Willebrand disease (VWD), which is defined as a partial deficiency of functionally normal VWF, approximately 35% of individuals do not have a putative mutation in the coding region, splice junctions, or proximal promoter of the VWF gene, suggesting that genes other than VWF may contribute to the pathophysiology of this disease. 12,13 VWF circulates in a tight, noncovalently linked complex with FVIII. The mean circulating half-lives of VWF and FVIII are 12 to 18 hours and12 hours, respectively, but details of the fate of both proteins are minimal. Evidence exists that cells in the li...

Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.

IntroductionBeta-thalassemia is a group of inherited hemolytic anemias and one of the most common genetic disorders in Thailand. The clinical spectrum of beta-thalassemia disease ranges from mild to severe clinical symptoms including mild beta-thalassemia intermedia (TI) and severe beta-thalassemia major (TM).ObjectiveThis study aimed to determine the correlation between beta-globin gene (HBB) mutations and their phenotypic manifestations by evaluating patients’ clinical characteristics, transfusion requirements, growth and hematologic parameters, and hemoglobin typing among pediatric patients treated at Phramongkutklao Hospital.Materials and methodsSeventy beta-thalassemia patients, including 63 with beta-thalassemia/hemoglobin E (HbE) and 7 with either homozygous or compound heterozygous beta-thalassemia, were enrolled in this study. Their clinical presentation, growth parameters and laboratory findings were reviewed and analyzed. The mean follow-up time was 10.52±5.62 years. Mutation analysis in each individual was performed using multiplex amplification refractory mutation system (M-ARMS), direct DNA sequencing of beta-globin gene and gap PCR for 3.4 kb deletion detection.ResultsAll 7 homozygous and compound heterozygous beta-thalassemia patients were classified in TM. Among 63 patients with beta-thalassemia/HbE, 58 were classified in TM and 4 were classified in TI. Mean age at diagnosis was 0.8±0.49 years for homozygous or compound heterozygous beta-thalassemia and 3.43±3.5 years for beta-thalassemia/HbE. The most common HBB mutation was HBB:c.126_129delCTTT [codon 41/42 (-TCTT)] found in 34 alleles (48.6%). The height for age was also lower in homozygous beta-thalassemia patients (<3rd percentile) compared to compound heterozygous beta-thalassemia patients (25–50th percentile).ConclusionThis study revealed a genotype–phenotype correlation of the most prevalent beta-thalassemia in Thai children using diagnostic capacity in genotypic analysis of HBB mutation. Our findings can provide a better prediction of clinical manifestation and severity by early identification of the type of the HBB mutations.

Backgroundα-Thalassemia, one of the major thalassemia types in Thailand, is caused by either deletion or non-deletional mutation of one or both α-globin genes. Inactivation of three α-globin genes causes hemoglobin H (Hb H) disease, and the combination of Hb H disease with heterozygous hemoglobin E (Hb E) results in AE Bart’s disease.ObjectiveThis study aimed to characterize the clinical and hematological manifestations of 76 pediatric patients with Hb H and AE Bart’s diseases treated at Phramongkutklao Hospital, a tertiary care center for thalassemia patients in central Thailand.Patients and methodsSeventy-six unrelated pediatric patients, 58 patients with Hb H disease and 18 patients with AE Bart’s disease, were enrolled in this study. Their clinical presentations, transfusion requirement, laboratory findings, and mutation analysis were retrospectively reviewed and analyzed.ResultsA total of 76 pediatric patients with Hb H and AE Bart’s diseases who mainly lived in central Thailand were included in this study. The clinical severities of patients with non-deletional mutations were more severe than those with deletional mutations. Eighty-six percent of patients with non-deletional AE Bart’s disease required more blood transfusion compared to 12.5% of patients with deletional AE Bart’s disease. Non-deletional AE Bart’s disease also had a history of urgent blood transfusion with the average of 6±0.9 times compared to 1±0.3 times in patients with deletional Hb H disease. The difference was statistically significant.ConclusionThis study revealed the differences in clinical spectrum between patients with Hb H disease and those with AE Bart’s disease in central Thailand. The differentiation of α-thalassemia is essential for appropriate management of patients. The molecular diagnosis is useful for diagnostic confirmation and genotype–phenotype correlation.

Our study emphasizes the need to test selected female patients with complete or incomplete disease expression for X-linked disorders even in the absence of a family history.