The E326K mutation and Gaucher disease: mutation or polymorphism?

Gaucher disease is caused by mutations in the gene for human glucocerebrosidase, a lysosomal enzyme involved in the intracellular hydrolysis of glucosylceramide. While over 150 different glucocerebrosidase mutations have been identified in patients with Gaucher disease, not all reported mutations have been fully characterized as being causative. One such mutation is the E326K mutation, which results from a G to A nucleotide substitution at genomic position 6195 and has been identified in patients with type 1, type 2 and type 3 Gaucher disease. However, in each instance, the E326K mutation was found on the same allele with another glucocerebrosidase mutation. Utilizing polymerase chain reaction (PCR) screening and restriction digestions of both patients with Gaucher disease and normal controls, we identified the E326K allele in both groups. Of the 310 alleles screened from patients with Gaucher disease, the E326K mutation was detected in four alleles (1.3%). In addition, screening for the E326K mutation among normal controls from a random population revealed that three alleles among 316 screened (0.9%) also carried the E326K mutation. In the normal controls with the E326K allele, the glucocerebrosidase gene was completely sequenced, but no additional mutations were found. Because the E326K mutation may be a polymorphism, we caution that a careful examination of any allele with this mutation should be performed to check for the presence of other glucocerebrosidase mutations.     

Was the C282Y mutation an Irish Gaelic mutation that the Vikings help disseminate?

The C282Y mutation is held to have arisen in either a Celtic or a Viking ancestor some 60 generations ago. While the Scandinavians have a high frequency of C282Y, the Irish have the highest frequency of the C282Y mutation in the world. However testing of the Irish people for C282Y has been patchy. The true frequency of the C282Y mutation in Ireland and specifically in the relatively isolated western province of Connaught is unknown. Establishment of the C282Y frequency in the Irish male population of Connaught with traditional Irish surnames, a group which has a virtual fixation for Y chromosome R1b3, could help establish C282Y as an Irish mutation. Elucidation of greater C282Y haplotype diversity for the Irish as opposed to the Scandinavians would indicate the Irish as the likely source population for C282Y. Taken together, linking of C282Y to the Irish Gaelic male population of Connaught and establishment of an Irish origin of the C282Y mutation would point to dissemination of the C282Y mutation by Viking raiders and colonizers.     

Immunodeficiency mutation databases — a new research tool

Recently, international study groups have collected mutations for X-linked immunodeficiency diseases. In this issue of Immunology Today five databases are reported, comprising mutations from over 1000 patients, facilitating detailed analysis of genetic, immunological, biochemical and structural parameters.     

The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant?

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of serositis. To date more then 18 mutations responsible for the disease were identified in the MEFV gene, one such a mutation is E148Q in exon 2 of the gene. While screening FMF patients for mutations in the MEFV gene, we have identified 2 individuals parents of 2 unrelated FMF patients, who were homozygous for E148Q mutation. Upon clinical examination they were absolutely disease free and therefore raised the possibility that this mutation is a benign polymorphism rather than a mutation causing disease. To further investigate the role of the E148Q in FMF we analyzed 25 parents of FMF patients and a control group of 70 individuals, Jews of Moroccan extraction to match for ethnicity of the patients. The rate of E148Q in the control group was 6.4%, being 7.8% among the patient group. Among the parents group (obligatory carriers), in addition to the 2 parents that were homozygous E148Q, in 2 families one of the parents was heterozygote for E148Q but transmitted the other allele (apparently with unknown FMF mutation) to the affected child. Two healthy sibs of one of the E148Q homozygous were also homozygous E148Q. These observations are not in accordance to the notion that E148Q is a mutation causing disease.     

Somatic mutation: a cause of sporadic neurodegenerative diseases?

The major causes of the common neurodegenerative diseases remain unknown. Alzheimer's disease, Parkinson's disease and motor neuron disease occur in both sporadic and familial forms, and mutations are progressively being found in families with these disorders. However, attempts to find causative mutations in blood DNA from the sporadic forms of the diseases have proved fruitless. It is hypothesised that this is because the causative mutations are found only in the cells in the central nervous system that are affected by the disease. These mutations arise in the developing embryo in progenitor cells of neurons or glia. The diseases are not passed to offspring since the mutations are not present in the germ-line. To find somatic mutations, the affected central nervous system cells need to be separated out and submitted to DNA analysis.     

Did the GJB2 35delG mutation originate in Iran?

Mutations in GJB2 are a major cause of autosomal recessive non-syndromic hearing loss (ARNSHL) in many populations. A single mutation of this gene (35delG) accounts for approximately 70% of GJB2 mutations that are associated with ARNSHL in Caucasians in many European countries and also in Iranian. In this study, we used PCR and restriction digestion to genotype five single nucleotide polymorphisms (SNPs) that define the genetic background of the 35delG mutation over an interval of 98 Kbp that includes the coding and flanking regions of GJB2. Two microsatellite markers, D13S175 and D13S141, were also analyzed in patients and controls. These data suggest that the 35delG mutation originated in northern Iran.     

Selection and mutation for α Thalassemia in nonmalarial and malarial environments

α thalassemia is the result of the loss of one or both copies of the two human α globin genes. α thalassemia appears to be the most common monogenic disease in the world and is in high frequency where malaria is, or has been, endemic. In nonmalarial environments, α thalassemia is rare and its frequency can be explained by a balance of deletional mutation and purifying selection. In malarial environments, the loss of one or two copies of the four α globin genes in normal diploid genotypes confers resistance (lower mortality) to malaria. Fitness estimates from data from Kenyan and Papua New Guinea populations are used to predict the increase in the --α haplotype (with one deleted gene). The frequency of double deletions (-- haplotypes) is higher in some Asian populations than that of single deletions. In this case, heterozygotes with normal αα haplotypes are expected to have the highest fitness. Overall, this population genetic examination provides an evolutionary framework for understanding the worldwide frequency of α thalassemia and the deletions that cause it in both nonmalarial and malarial environments.     

Do carriers of POLG mutation W748S have disease manifestations?

Mitochondrial recessive ataxia syndrome (MIRAS) is a common cause of autosomal recessive juvenile- or adult-onset ataxia, at least in Scandinavia. MIRAS patients are homozygous or compound heterozygous for POLG mutations W748S and A467T. Because many first-degree relatives of MIRAS patients in the studied families have reported neurological symptoms and some recent studies have suggested dominant negative effect of these mutations, a careful family study of heterozygotes was needed. We investigated all available members of the original large MIRAS family with W748S mutation. Neurological symptoms and signs were present in a number of carriers, but clearly defined neurological diseases did not segregate consistently with the mutation. Sensory polyneuropathy as a subclinical finding was observed in the majority of carriers examined. By positron emission tomography, cerebral glucose metabolism was moderately reduced in two out of four heterozygotes compared with severe reduction in one MIRAS patient. In conclusion, W748S heterozygotes showed no clinically manifesting phenotype.     

Novel nonsense IL-12Rβ1 mutation associated with recurrent tuberculosis

Immunologic Research - The interleukin (IL)-12/interferon(IFN)γ axis plays an important role in the control of mycobacterial diseases as demonstrated by the increased susceptibility to...     

Sequence variation in mitochondrial complex I genes: mutation or polymorphism?

Background

Defects of the mitochondrial genome are recognised as common causes of genetic disease. Sequencing of large portions or even the entire mitochondrial genome is routine in many laboratories for the investigation of mitochondrial disease. However, establishing whether a detected sequence change is polymorphic or pathogenic is still a major difficulty because of its highly polymorphic nature. This has major implications for the patient and the family.

Objective

To describe a scoring system for determining the likelihood that a given sequence variant in one of the seven mitochondrially encoded complex I (MTND) genes is truly pathogenic.

Results

The scoring system was applied to 50 reported MTND mutations. Using this system, 21 of the mutations analysed fell into the group of neutral sequence variants, 10 were classified as possibly pathogenic, three as probably pathogenic, and 16 as almost certainly pathogenic.

Conclusions

The proposed scoring system should advance the interpretation of sequence variants and ensure that candidate pathogenic mutations are rigorously investigated.     

The enigma of the E326K mutation in acid β-glucocerebrosidase

A large number of mutations, and several polymorphisms, have been characterized in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase, the activity of which is impaired in Gaucher disease. In this communication we summarize published and new data concerning biochemical characterization of the E326K amino acid change (1093G>A in the GBA1 cDNA) in tissue culture and its association with Parkinson disease, suggesting it is a disease causing mutation and not merely a polymorphism in the GBA gene.