The Frequency in Japan of Carriers of the Rare “Recessive” Gene Causing Acatalasemia

Hamilton, Howard B.; Neel, James V.; Kobara, Thomas Y.; Ozaki, Kyoko

doi:10.1172/jci104446

Cited by 32 publications

(5 citation statements)

References 9 publications

(9 reference statements)

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“…Notable exceptions to this have been surveys to determine heterozygote frequencies directly for acatalasemia (8) and TaySachs disease (9). By contrast, the nine enzymes that have been the objective of this study were not chosen specifically because they are associated with a disease (although for seven ofthe nine enzymes deficiency diseases are known) but because of their relatively restricted variation in level of enzyme activity among individuals (10), which renders these enzymes favorable subjects for the study of deficiency variants.…”

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confidence: 99%

Frequency of enzyme deficiency variants in erythrocytes of newborn infants.

Mohrenweiser¹

1981

Proc. Natl. Acad. Sci. U.S.A.

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The frequency of enzyme deficiency variants, defined as alleles whose products are either absent or almost devoid of normal activity in erythrocytes, was determined for nine erythrocyte enzymes in some 675 newborn infants and in approximately 200 adults. Examples of this type of genetic abnormality, which in the homozygous condition are often associated with significant health consequences, were detected for seven of the nine enzymes studied. Fifteen inherited enzyme deficiency variants in 6142 determinations from the newborn population and 5 variants in 1809 determinations from adults were identified. Seven of the deficiency variants involved triosephosphate isomerase, a frequency of0.01 in the newborn population. The average frequency of 2.4/1000 is 2-3 times the frequency observed for rare electrophoretic variants of erythrocyte enzymes in this same population.Recent years have witnessed a great wave ofenthusiasm for the electrophoretic approach as a means of defining the frequency of "occult" variation in a random sample of a plant or animal population. Strong tool though this has been, it has been recognized that this technique reveals only the tip of the iceberg, in that it fails to detect variants not associated with a charge change in the molecule under scrutiny, and it usually fails to detect variation characterized by actual or functional loss ofgene product. In this paper we will describe the results of an effort to determine the frequency ofgenetic variants resulting in total or near-total loss of activity for a series of nine human erythrocyte enzymes. We have previously reported on the frequency of rare electrophoretic variants in this sample, and in a companion paper (1) we will report the results of studies designed to estimate, for the same population and enzymes, the frequency of genetic variants exhibiting alterations in thermostability. Both investigations were undertaken in the context ofan effort to move the study of human mutation rates to the biochemical level (2).In 1932, Muller (3), in an attempt to classify types of genetic variation, distinguished between amorphs, hypomorphs, and hypermorphs. An amorph was a variant in which gene product (as then understood) was totally absent. In retrospect, Garrod in 1909 (4) defined the first amorph in man. Currently, over 100 metabolic diseases have been described in which a specific enzyme defect, either an amorph or a hypomorph in the terminology of Muller, has been identified (5-7). Almost all of these defects are detectable in the heterozygote or "carrier" individual through a significant reduction in enzyme activity, usually approaching 50% of the expected value (6). Although we have been unable to trace the origin of the term, these deficiences and in particular the amorphs, are often called "nulls."Our knowledge of the population frequency of null alleles in humans has been largely indirect, in the sense that most estimates take as their point of departure a recessively inherited disease characterized by loss of enzyme activity, fo...

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confidence: 99%

Frequency of enzyme deficiency variants in erythrocytes of newborn infants.

Mohrenweiser¹

1981

Proc. Natl. Acad. Sci. U.S.A.

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“…Rare disease prevalence is widely thought to be underestimated and is complicated by heterogeneous phenotypes, digenic and polygenic inheritance, and differences between subpopulations [ 111 , 112 ]. For example, acatalasemia/hypocatalasemia prevalence has been estimated at over 2% in some Asian populations [ 113 , 114 ], making it important to consider individual ancestry when interpreting catalase variants. In a polygenic inheritance model, it is possible that a specific combination of variants that are each individually more common than the disease prevalence together create the disease-causative effect.…”

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confidence: 99%

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

Berger

Arafat

Chandrakasan

et al. 2022

JPM

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Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if targeted RNA sequencing could provide similar benefits for primary immunodeficiencies (PIDs) and very early-onset inflammatory bowel disease (VEOIBD), both of which are difficult to diagnose due to high heterogeneity and variable severity. We performed targeted RNA sequencing of a panel of 260 immune-related genes for a cohort of 13 patients (seven suspected PID cases and six VEOIBD) and analyzed variants, splicing, and exon usage. Exonic variants were identified in seven cases, some of which had been previously prioritized by exome sequencing. For four cases, allele specific expression or lack thereof provided additional insights into possible disease mechanisms. In addition, we identified five instances of aberrant splicing associated with four variants. Three of these variants had been previously classified as benign in ClinVar based on population frequency. Digenic or oligogenic inheritance is suggested for at least two patients. In addition to validating the use of targeted RNA sequencing, our results show that rare disease research will benefit from incorporating contributing genetic factors into the diagnostic approach.

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“…Haemoglobin electrophoresis, visualization of the carbonic anhydrase isozymes by starch-gel electrophoresis, and determination of the total red cell carbonic anhydrase activity were performed by previously reported methods (Weatherall, 1965 ;Weatherall and McIntyre, 1967). Red cell catalase activity was determined by the method of Hamilton et al (1961). Titration of the I antigen was carried out with serum from a patient with a high titre of cold agglutinins against cells from at least five adult and cord blood samples as a control for each determination.…”

Section: Methodsmentioning

confidence: 99%