Identification of mutations in two major mRNA isoforms of the Chediak- Higashi syndrome gene in human and mouse

Abstract

Chediak-Higashi syndrome is an autosomal recessive, immune deficiency disorder of human (CHS) and mouse (beige, bg) that is characterized by abnormal intracellular protein transport to, and from, the lysosome. Recent reports have described the identification of homologous genes that are mutated in human CHS and bg mice. Here we report the sequences of two major mRNA isoforms of the CHS gene in human and mouse. These isoforms differ both in size and in sequence at the 3' end of their coding domains, with the smaller isoform (approximately 5.8 kb) arising from incomplete splicing and reading through an intron. These mRNAs also differ in tissue distribution of transcription and in predicted biological properties. Novel mutations were identified within the region of the coding domain common to both isoforms in three CHS patients: C-->T transitions that generated stop codons (R50X and Q1029X) were found in two patients, and a novel frameshift mutation (deletion of nucleotides 3073 and 3074 of the coding domain) was found in a third. Northern blots of lymphoblastoid mRNA from CHS patients revealed loss of the largest transcript (approximately 13.5 kb) in two of seven CHS patients, while the small mRNA was undiminished in abundance. These results suggest that the small isoform alone cannot complement Chediak-Higashi syndrome.

Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D

“…9,25,32 ND indicates no data; NA, not applicable; CSF, cerebrospinal fluid; CNS, central nervous system; and HSCT, hematopoietic stem cell transplantation. *Defective: Յ 10 lytic units.…”

“…Ͼ C, p.Leu881Pro predicted to be pathogenic using 2 different protein prediction programs (PolyPhen, SIFT 30,31 ), whereas the other mutations are previously described. 9,25,32 ND indicates no data; NA, not applicable; CSF, cerebrospinal fluid; CNS, central nervous system; and HSCT, hematopoietic stem cell transplantation. *Defective: Յ 10 lytic units.…”

“…22,23 In addition, Griscelli syndrome type 2 and Chediaki-Higashi syndrome, both with autosomal recessive inheritance and caused by mutations in RAB27A and LYST, respectively, are associated with development of HLH in addition to manifesting partial albinism. 24,25 The relative frequency of mutations in various genes causative of FHL differs among ethnicities. 26,27 With the advance of knowledge concerning genetic associations with FHL, a molecular diagnosis can be attained for an increasing proportion of patients.…”

Lung defences: an overview

“…Defects in neutrophil function lead to severe disorders. In Chediak-Higaschi disease, a congenital immunological defect known to be accompanied by severe pyogenic infections, the granules cannot package the protein elastase or the cathepsin-G superfamily [50]. In chronic granulomatous diseases, affected individuals are susceptible to bacterial infections because their phagocytic cells are unable to generate the products of respiratory burst [51].…”

Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1

“…Mutation analyses of the CHS gene have been somewhat hindered by the large size of the CHS cDNA (13.5 kb), and thus far, only eight pathologic mutations have been identified, all of which leading to a truncated CHS protein. 9,11,12 We herein report the case of a cytogenetically normal male affected with CHS as a result of homozygosity for mutation of the LYST gene. Homozygosity for the LYST gene was the result of maternal disomy of the entire chromosome 1.…”