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Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.

Succinyl‐CoA synthetase or succinate‐CoA ligase deficiency can result from biallelic mutations in SUCLG1 gene that encodes for the alpha subunit of the succinyl‐CoA synthetase. Mutations in this gene were initially associated with fatal infantile lactic acidosis. We describe an individual with a novel biallelic pathogenic mutation in SUCLG1 with a less severe phenotype dominated by behavioral problems. The mutation was identified to be c.512A>G corresponding to a p.Asn171Ser change in the protein. The liquid chromatography tandem mass spectrometry‐based enzyme activity assay on cultured fibroblasts revealed a markedly reduced activity of succinyl‐CoA synthetase enzyme when both ATP and GTP were substrates, affecting both ADP‐forming and GDP‐forming functions of the enzyme.

Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B 12 (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings 1 . Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood 2 . The cblC locus was mapped to chromosome region 1p by linkage analysis 3 . We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.

This commentary is based on the key note address given by Jordan Lerner-Ellis at the annual symposium of the Society for the Study of Inborn Errors of Metabolism, held in Geneva, Switzerland in August 2011. The content of the address was developed from a series of discussions with seven clinicians and medical geneticists, all having a long-time interest in genetic testing and genomic medicine (the interviews were not intended to be a forum for the introduction of new data). All participants were asked to offer their views on five questions: the benefits of using whole genome sequencing (WGS) in the clinic; the corresponding risks; the limitations on its wider use; the interviewees’ particular interests in using WGS in their practice; and projected timelines for successful adoption in clinical medicine.

The genetic basis of a defect in the metabolism of vitamin B 12 (the cblD defect) was studied in cultured skin fibroblasts from seven patients with the defect. The defect was localized to chromosome 2q23.2, and a candidate gene (designated MMADHC ) was identified in this region. Mutations in MMADHC were found in all seven patients. Transfection of the gene into fibroblasts from patients rescued the affected metabolic pathways. 12 The genetic basis of a defect in the metabolism of vitamin B 12 (the cblD defect) was studied in seven patients with the defect. The defect was localized to chromosome 2q23.2, and a candidate gene was identified. Vitamin B 12 (cobalamin) is essential for normal development and survival in humans and must be obtained from animal products or supplements. Inside the cell, it is converted to two active cofactors, adenosylcobalamin and methylcobalamin (Figure 1). 1 Adenosylcobalamin is the coenzyme for mitochondrial methylmalonyl–coenzyme A mutase, which converts L-methylmalonyl–coenzyme A to succinyl–coenzyme A and is involved in catabolism of odd-chain fatty acids and some amino acids. Methylcobalamin is the coenzyme for cytosolic methionine synthase, which converts homocysteine to methionine and is essential for normal one-carbon metabolism, which is in turn involved in vital cellular processes such as methylation and DNA . . .

Mutations in the MMAA gene on human chromosome 4q31.21 result in vitamin B12‐responsive methylmalonic aciduria (cblA complementation group) due to deficiency in the synthesis of adenosylcobalamin. Genomic DNA from 37 cblA patients, diagnosed on the basis of cellular adenosylcobalamin synthesis, methylmalonyl–coenzyme A (CoA) mutase function, and complementation analysis, was analyzed for deleterious mutations in the MMAA gene by DNA sequencing of exons and flanking sequences. A total of 18 novel mutations were identified, bringing the total number of mutations identified in 37 cblA patients to 22. A total of 13 mutations result in premature stop codons; three are splice site defects; and six are missense mutations that occur at highly conserved residues. Eight of these mutations were common to two or more individuals. One mutation, c.433C>T (R145X), represents 43% of pathogenic alleles and a common haplotype was identified. Restriction endonuclease or heteroduplex diagnostic tests were designed to confirm mutations. None of the sequence changes identified in cblA patients were found in 100 alleles from unrelated control individuals. Hum Mutat 24:509–516, 2004. © 2004 Wiley‐Liss, Inc.

The original article to which this Erratum refers was published in Human Mutation 24:509–516 Human Mutation(2004) 24(6) 509–516