Apparent genotype–phenotype correlation in childhood,adolescent, and adult Chediak‐Higashi syndrome

Chediak‐Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10–15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype–phenotype relationship among the various clinical forms of CHS. © 2002 Wiley‐Liss, Inc.     

一个Chediak-Higashi综合征家系CHS1/LYST基因新变异

目的对1个旁系血亲婚配的Chediak-Higashi综合征家系的CHS1/LYST基因进行变异检测,探讨LYST基因变异与临床表型的关系。方法收集临床资料及家系调查,分析2例患者的临床资料和实验室检查结果。提取患者外周血DNA及父母等16名亲属指甲的DNA,采用外显子组测序分析患者的致病基因,根据基因变异点对亲属相应位点做Sanger测序,确认携带者。结果该家系中2例患者临床均有皮肤部分白化及免疫缺陷,表现为反复严重感染、出血倾向且发生嗜血现象,骨髓细胞及血涂片检查均出现粗大的嗜酸性包涵体颗粒。LYST基因第34外显子存在c.8782C>T(p.Gln2928*)纯合无义变异,与其表型相关,且该变异为新变异点。确认6名表型正常的家系成员的LYST基因存在与先证者相同的杂合变异,另10名表型正常的家系成员则均未检测到该变异。结论基因变异分析结果丰富了Chediak-Higashi综合征致病基因的变异谱,为临床明确病因提供了重要依据,并为家系遗传咨询和产前诊断提供了参考依据。     

Analysis of clinical characteristics and genetic mutation in a pedigree affected with Chediak-Higashi syndromeCSCD

Objective To explore the genetic basis for a pedigree affected with Chediak-Higashi syndrome (CHS). Methods Clinical data of two CHS patients from the pedigree was collected and analyzed. Targeted next generation sequencing and Sanger sequencing were conducted to detect potential mutation of the LYST gene. Results Both patients presented immunodeficiency, oculocutaneous albinism, and acidophilic inclusion body on bone marrow and blood smears. A homozygous c. 6077- 6078insA (p. Tyr2026Terfs) mutation was detected in the LYST gene in both patients. Conclusion Genetic testing can play an important role in the diagnosis of CHS. © 2018 West China University of Medical Sciences. All rights reserved.     

The lysosomal trafficking regulator is necessary for normal wound healing

Non-healing wounds are a major threat to public health throughout the United States. Tissue healing is complex multifactorial process that requires synchronicity of several cell types. Endolysosomal trafficking, which contributes to various cell functions from protein degradation to plasma membrane repair, is an understudied process in the context of wound healing. The lysosomal trafficking regulator protein (LYST) is an essential protein of the endolysosomal system through an indeterminate mechanism. In this study, we examine the impact of impaired LYST function both in vitro with primary LYST mutant fibroblasts as well as in vivo with an excisional wound model. The wound model shows that LYST mutant mice have impaired wound healing in the form of delayed epithelialization and collagen deposition, independent of macrophage infiltration and polarisation. We show that LYST mutation confers a deficit in MCP-1, IGF-1, and IGFBP-2 secretion in beige fibroblasts, which are critical factors in normal wound healing. Identifying the mechanism of LYST function is important for understanding normal wound biology, which may facilitate the development of strategies to address problem wound healing.     

A novel single point mutation of the LYST gene in two siblings with different phenotypic features of Chediak Higashi syndrome

Chediak Higashi syndrome (CHS) is an autosomal-recessive disorder characterized by oculocutaneous albinism, recurrent infections and a progressive primary neurological disease. Here, we describe two siblings with CHS due to a novel homozygous R1836X mutation in the LYST gene associated with loss of NK cell degranulation and cytotoxicity. While one sibling was born with fair skin and hair and died of hemophagocytic lymphohistiocytosis (HLH) at 5 months of age, the other sibling had dark black hair and skin and developed HLH at the age of 4 years.     

LYST蛋白表达量在Chediak-Higashi综合征临床诊断中的应用

目的 探讨LYST基因突变导致的蛋白差异表达在罕见病Chediak-Higashi综合征(Chediak-Higashi syndrome,CHS)中的临床诊断应用价值.方法 利用免疫印迹(Western blotting,WB)检测CHS患儿、患儿直系家属以及健康志愿者的外周血白细胞中LYST蛋白表达量.结果 患儿白细胞中LYST蛋白出现两种截短体(p.R1104X、p.N2535KfsX2),呈高表达,而患儿直系家属以及健康志愿者白细胞中未检测到LYST蛋白表达.结论 CHS患儿外周血白细胞LYST截短体表达量较健康人显著增加.因此,免疫印迹检测LYST截短体的高表达可以作为辅助临床诊断CHS的一种新方法.