Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Motor Neuron Disease
Position: (GRCh38/hg38):Chr19:44908684 T>C
Position: (GRCh37/hg19):Chr19:45411941 T>C
Position: (GRCh38/hg38):Chr19:4490882 C>T
Position: (GRCh37/hg19):Chr19:45412079 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
Codon Change: CGC to TGC, TGC to CGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This rare genotype is a combination of an arginine at position 130 and a cysteine at position 176 on the same chromosome, the reverse of the common APOE3 allele, hence named APOE3r. Of the seven carriers reported to date, four have been studied in the clinic. Two had neurological disorders and two were ostensibly neurologically healthy. No lipid abnormalities in blood were found in any of these four carriers.

APOE3r was first reported in an autistic Italian boy of Caucasian ancestry and his mother (Persico et al., 2004). On his other chromosome, the boy carried the APOE2 allele, while the mother carried the APOE3 allele. By age 2, the boy showed delays in his mental development, particularly in his social abilities. At age 6, he remained non-verbal, lacked awareness of other people, displayed stereotyped movements, and adopted unusual postures. Although an MRI of his brain revealed no abnormalities, awake EEG recordings showed diffuse slowing of background activity. His triglyceride and cholesterol levels in plasma were normal. No clinical information was reported for the mother.

The second carrier with a neurological condition was an elderly man diagnosed with motor neuron disease (Seripa et al., 2007). At 76 years of age, he developed leg weakness, followed by hand weakness, dysphagia, dysarthria, bradykinesia, and vertical supranuclear gaze palsy. His symptoms worsened, and measurements of motor-evoked potentials revealed a dysfunction of central motor pathways. As reported for other carriers, his lipid and lipoprotein profiles in plasma were normal. Unlike other carriers, however, he harbored the APOE4 allele on his other chromosome. Both his daughter and son were non-carriers, having inherited his APOE4 allele. Of note, there was no known history of either motor neuron disease or lipid abnormalities in his family, including his parents.

The APOE3r genotype was also reported in a healthy 70 year-old Yoruba woman from Nigeria (Murrell et al., 2006). Levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in blood were normal, as was her lipoprotein profile as revealed by gel filtration and agarose gel electrophoresis. The only other member of her family who was genotyped, her brother, did not have this genotype.

The prevalence of APOE3r remains uncertain, and may in fact be higher than suggested by the very small number of published carriers, since the genotype can be miscalled as APOE2/E4 by most current genotyping methods, as well as by earlier protein-based methods. It is predicted to be rare because the recombination event required to create this genotype in an APOE2/E4 heterozygote, a rare genotype itself, is unlikely to occur often (Seripa et al., 2007; Belloy et al., 2019). APOE3r could also arise as an additional substitution on an APOE2 or APOE4 background.

Interestingly, a study of 48,855 individuals from the UK Biobank suggests the frequency of APOE3r may vary between populations of different ancestries (Huang et al., 2021). In this study, two individuals with the APOE3r genotype were identified. They were seemingly unrelated but were both of African ancestry. These authors also identified the genotype in an African Yoruba individual from the 1000 Genomes Project. The frequency of the genotype in this population was reported as 0.005 given its presence in one of only 216 sequenced individuals.

Biological Effect

The biological effect of this genotype is unknown. Although in humans no lipid abnormalities in blood have been detected, an unpublished observation by Robert Mahley and colleagues indicated mice carrying this genotype had elevated levels of cholesterol in blood (see Seripa et al., 2007).

Nomenclature Notes

Alzforum named this genotype following Human Genome Variation Society (HGVS) guidelines. Note that it is distinct from [R176C];[C130R] in which carriers have the two common APOE alleles, R176C (APOE2), and C130R (APOE4), on different chromosomes.  It was initially named APOE3r to denote the reverse order of the substitutions at positions 130 and 176 compared with APOE3 (Persico et al., 2004). It has also been referred to as APOE*1 (Huang et al., 2021) and APOE1Y (Murrell et al., 2006), where the 1 reflects its relationship to genotypes APOE2 and APOE3 as another derivative of the ancestral APOE4 allele, and in the latter case, the Y stands for Yoruba.

Comments

1. • Dylan Williams
     University College London
   • Posted: 10 Jan 2023

   ApoE3r may not be particularly rare in individuals of Yoruba ethnicity. Using whole-exome sequencing data from a subset of approximately 48,000 UK Biobank participants, Huang et al. identified this haplotype in ~0.5 percent of individuals of Yoruba descent. With the release of more exome sequencing data (and the impending release of whole-genome sequencing data on almost all of UK Biobank in 2023), further analysis will help confirm the frequency of this haplotype in Yoruba individuals with more precision.

   References:

   Huang J, Pallotti S, Zhou Q, Kleber M, Xin X, King DA, Napolioni V. PERHAPS: Paired-End short Reads-based HAPlotyping from next-generation Sequencing data. Brief Bioinform. 2021 Jul 20;22(4) PubMed.

   View all comments by Dylan Williams

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References

Mutations Citations

1. APOE [R176C];[C130R] (ApoE2/4)
2. APOE R176C (ApoE2)
3. APOE C130R (ApoE4)

Paper Citations

1. Persico AM, D'Agruma L, Zelante L, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, Montecchi F, Elia M, Palermo M, Rabinowitz D, Pascucci T, Puglisi-Allegra S, Reichelt KL, Muscarella L, Guarnieri V, Melgari JM, Conciatori M, Keller F. Enhanced APOE2 transmission rates in families with autistic probands. Psychiatr Genet. 2004 Jun;14(2):73-82. PubMed.
2. Seripa D, Matera MG, Daniele A, Bizzarro A, Rinaldi M, Gravina C, Bisceglia L, Corbo RM, Panza F, Solfrizzi V, Fazio VM, Forno GD, Masullo C, Dallapiccola B, Pilotto A. The missing ApoE allele. Ann Hum Genet. 2007 Jul;71(Pt 4):496-500. Epub 2007 Jan 22 PubMed.
3. Murrell JR, Price BM, Baiyewu O, Gureje O, Deeg M, Hendrie H, Ogunniyi A, Hall K. The fourth apolipoprotein E haplotype found in the Yoruba of Ibadan. Am J Med Genet B Neuropsychiatr Genet. 2006 Jun 5;141B(4):426-7. PubMed.
4. Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
5. Huang J, Pallotti S, Zhou Q, Kleber M, Xin X, King DA, Napolioni V. PERHAPS: Paired-End short Reads-based HAPlotyping from next-generation Sequencing data. Brief Bioinform. 2021 Jul 20;22(4) PubMed.

Further Reading

No Available Further Reading