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Cited by 33Metabolism and Genetic DisordersGenomics and Rare DiseasesGlycogen Storage Diseases and Myoclonus

Dominant versus recessive: Molecular mechanisms in metabolic disease

Zschocke, Johannes·2008·Journal of Inherited Metabolic Disease
DOI 10.1007/s10545-008-1016-5
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Abstract

Summary: Inborn errors of metabolism used to be regarded as simple monogenic traits, but a closer look at how different alleles of a gene determine different phenotypes shows that the molecular mechanisms in the individual case are often complicated. Most metabolic disorders represent a spectrum of phenotypes from normal via attenuated to severe (and sometimes prenatally fatal), and disease manifestation is often influenced by other specific genetic or exogenous factors. The terms ‘dominant’ or ‘recessive’ relate to the functional consequences of differing alleles in the (compound) heterozygous individual; the terms are irrelevant for homozygous individuals and inappropriate for X‐linked disorders. Mutations affecting the same amino acid residue may be associated with different inheritance patterns. True dominant inheritance in metabolism is rare; it may be found e.g. in tightly regulated biosynthetic pathways or when minor changes in metabolite concentrations have a functional effect. Some disorders such as erythropoietic protoporphyria show pseudodominant inheritance due to prevalent loss‐of‐function polymorphisms in the general population and are better acknowledged as recessive traits. The term ‘variable expressivity’ is not helpful with regard to autosomal recessive disorders when variable phenotypes are explained by different mutations in the respective gene. Clonal unmasking of a heterozygous mutation through somatic loss of the second allele, the main pathomechanism in inherited tumour predisposition syndromes, is rare in metabolic disorders, but focal congenital hyperinsulinism is a notable exception. Somatic mosaicism for an OTC gene mutation is given as an example of an apparently heterozygous mutation pattern in a boy with an X‐linked disease.

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Crossref · 10.1007/s10545-008-1016-5

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  • Rare variant effects can manifest as compound heterozygosity, the unmasking of deleterious variants through deletions on a homologous chromosome, and other haplotype context-dependent phenomena.

    “Rare variant effects can manifest as compound heterozygosity,90 the ‘unmasking’ of deleterious variants via deletions on a homologous chromosome12, and other haplotype context-dependent phenomena.”

    From Statistical analysis strategies for association studies involving rare variants (2010) · cites this paper as [90]

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Authors
Zschocke, J.
Affiliations
Innsbruck Medical University (AT)
Corresponding author
Zschocke, Johannes
ORCID
Zschocke, Johannes
Venue
Journal of Inherited Metabolic Disease
Publisher
Wiley
Published
2008-10
Volume
31
Issue
5
Pages
599-618
ISSN
  • 0141-8955 (ISSN-L)
  • 1573-2665
DOI
10.1007/s10545-008-1016-5
OpenAlex
W1994767991
Cited by
33
References
140
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2022: 4 · 2020: 4 · 2019: 1 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 3 · 2012: 1
FWCI
0.38
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 20 d)
Locations
  • Journal of Inherited Metabolic Disease (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
Keywords
inborn errors of metabolism, dominant inheritance, recessive inheritance, compound heterozygosity, variable expressivity, erythropoietic protoporphyria, pseudodominant inheritance, somatic mosaicism, OTC gene, X-linked disorders, loss-of-function polymorphism, genotype-phenotype correlation
MeSH terms
Female, Genes, Dominant, Genes, Recessive, Humans, Male, Metabolism, Inborn Errors, Models, Genetic, Mutation, Genetic Diseases, X-Linked, History, 20th Century

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