UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis

Yoon, Hoi Soo; Kim, Hee Jin; Yoo, Keon Hee; Sung, Ki Woong; Koo, Hong Hoe; Kang, Hyoung Jin; Shin, Hee Young; Ahn, Hyo Seop; Kim, Ji Yoon; Lim, Young Tak; Bae, Keun Wook; Lee, Ki O.; Shin, Ji Sook; Lee, Seung Tae; Chung, Hae Sun; Kim, Sun Hee; Park, Chan Jeoung; Sook, Hyun; Im, Ho Joon; Seo, Jong Jin

doi:10.3324/haematol.2009.016949

Cited by 48 publications

(56 citation statements)

References 31 publications

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“…These low frequencies are accounted for by the unexpected predominance of UNC13D mutations (85% in a recent study) in Korean patients with FHL [5]. Second, a specific mutation, c.1090_1091delCT, is the most prevalent PRF1 mutation in Korean and Japanese patients, compared with that in other ethnic groups [56789]. Interestingly, this type of PRF1 mutation shares the same nucleotide region as the mutation observed in our patient (c.1091T>G).…”

supporting

confidence: 48%

Familial Hemophagocytic Lymphohistiocytosis Type 2 in a Korean Infant With Compound Heterozygous PRF1 Defects Involving a PRF1 Mutation, c.1091T>G

et al. 2017

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supporting

confidence: 48%

Familial Hemophagocytic Lymphohistiocytosis Type 2 in a Korean Infant With Compound Heterozygous PRF1 Defects Involving a PRF1 Mutation, c.1091T>G

et al. 2017

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“…The genes ACOX1 (the acyl-coenzyme A oxidase 1) and UNC13D (Caenorhabditis elegans unc-13 homolog D) play a key role in the metabolism of very long chain fatty acids and vesicle maturation. A deficiency in these genes leads to pseudoneonatal adrenoleukodystrophy, a rare neurological disorder characterized by the accumulation of very long chain fatty acids, neurological deterioration, diffuse leukodystrophy with progressive demyelination, brain atrophy and severe white matter abnormalities (Fournier et al, 1994;El Hajj et al, 2012), and familial hemophagocytic lymphohistiocytosis type 3 (FHLH-3), a rare and genetically heterogeneous disorder with an autosomal recessive inheritance characterized by uncontrolled proliferation, infiltration of activated lymphocytes and macrophages, overproduction of inflammatory cytokines and immune dysregulation from the defective function of cytotoxic lymphocytes, and abnormal imaging of the brain white matter (Fitzgerald and MacClain, 2003;Yoon et al, 2010).…”

Section: Genome-wide Association Studymentioning

confidence: 99%

Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology

Lin¹,

Huang

Tzeng

2015

Reviews in the Neurosciences

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AbstractLeukoaraiosis (LA), also called white matter lesions (WMLs) and white matter hyperintensities (WMHs), is a frequent neuroimaging finding commonly seen on magnetic resonance imaging brain scans of elderly people with prevalence ranging from 50% to 100%. Although it remains asymptomatic, LA is not considered to be benign, and it is showed to be related to a host of poor clinical outcomes and increases the risk of disability, dementia, depression, stroke, and the overall morbidity and mortality. Pathologically, LA is characterized by loss of myelin and axons, patchy demyelination, and denudation of ependyma in regions of WMH. Age and hypertension are the most importantly established risk factors for LA. However, the precise pathogenic mechanisms remain unclear. Together with the previous findings, our recent genetic results strongly supported that LA is associated with immune response and neuroinflammation. Therefore, we confidently hypothesized that LA was not only a common neuroimaging phenomenon in the elderly but also an emerging neuroinflammatory disorder in the central nervous system. This article focusing on neuroimaging classification, genetics basis, and putative molecular mechanism introduced the basic knowledge and current status of LA and put forward some of our research ideas and results from our molecular genetics research, which may pave the way for deciphering the putative pathogenic mechanism, risk factor, epigenetic index, and its application in diagnostic agents or drug target for prevention and treatment. Thus, it could provide clinicians and researchers with a specific and modern overview of LA to enable the understanding of recent progress and future directions in this illness.

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“…The fact that several FHL cases had only one UNC13D mutant allele demonstrated that conventional direct sequencing missed the other mutation [37]. Recently, synergistic defects of different molecules affecting cytotoxic lymphocyte degranulation were revealed in the pathogenesis of HLH [23].…”

Section: Discussionmentioning

confidence: 99%

Synergistic defects of UNC13D and AP3B1 leading to adult hemophagocytic lymphohistiocytosis

et al. 2015

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A 32-year-old man of non-consanguineous Chinese parentage, with high-grade fever, rash, joint pain, nausea, and vomiting, was diagnosed as adult-onset still's disease at his initial admission. Although prednisone had been taken, the patient presented with recurrent high-grade fever, rash, splenomegaly, hypertriglyceridemia, cryptogenic hepatitis, apparently elevated levels of serum ferritin(>20,000 μg/L), which met the proposed HLH diagnostic criteria, 2009. Sequence analysis of genomic DNA from the patient's peripheral blood demonstrated heterozygous for UNC13D mutation: c. 1232 G>A, and AP3B1 mutation: c. 1075 A>G, which were predicted to be pathogenic. Unfortunately, at the time, molecular confirmation results for HLH were obtained, and this patient had died from progressive HLH disease with multiple organ dysfunction syndrome caused by shock. FHL should be considered in the differential diagnosis of adults who present with adult-onset still's disease-like symptoms.

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UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis

Cited by 48 publications

References 31 publications

Familial Hemophagocytic Lymphohistiocytosis Type 2 in a Korean Infant With Compound Heterozygous PRF1 Defects Involving a PRF1 Mutation, c.1091T>G

Familial Hemophagocytic Lymphohistiocytosis Type 2 in a Korean Infant With Compound Heterozygous PRF1 Defects Involving a PRF1 Mutation, c.1091T>G

Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology

Synergistic defects of UNC13D and AP3B1 leading to adult hemophagocytic lymphohistiocytosis

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