Dominant versus recessive: molecular mechanisms in metabolic disease.

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