haploinsufficient

Haploinsufficiency is a genetic principle describing how a diploid organism may manifest an abnormal phenotype because a single functional copy of a gene does not produce enough gene product. In this situation, the loss or inactivation of the second allele reduces the amount of the gene product below a threshold required for normal function, leading to a dominant phenotype even though one allele remains intact.

It is often observed for dosage-sensitive genes, including many transcription factors and regulators of development. Mechanisms that cause haploinsufficiency include loss-of-function mutations (nonsense, frameshift, essential splice-site changes), deletions that remove part or all of a gene, or regulatory changes that lower transcription or translation. Haploinsufficiency is distinct from dominant-negative effects, in which a mutant protein interferes with the function of the wild-type protein, and from simple haplosufficiency, where a single copy suffices to maintain normal function.

Several well-documented human examples illustrate the concept. TBX5 haploinsufficiency causes Holt-Oram syndrome, affecting limbs and heart development. PAX6 haploinsufficiency leads to aniridia, a congenital eye condition. MECP2 haploinsufficiency underlies Rett syndrome in many females, reflecting X-linked dosage sensitivity and X-inactivation dynamics.

Clinically, haploinsufficiency informs genetic diagnosis and prognosis and influences approaches to therapy, including strategies aimed at restoring gene dosage or compensating downstream pathways. Research into haploinsufficient genes continues to map dosage-sensitive regions of the genome and to clarify tissue-specific thresholds for gene product requirements.