Haploinsufficiency describes a genetic situation where an individual possesses only one functional copy of a particular gene, and this single copy is not sufficient to produce the normal amount of protein needed for proper bodily function. Humans typically inherit two copies of each gene, one from each parent. When one of these copies is either missing or non-functional, the remaining single copy cannot compensate, leading to a specific set of observable traits or conditions.
Understanding the Genetic Mechanism
Our bodies rely on a precise amount of proteins, which are the working molecules produced from our genes, to carry out countless biological processes. Each gene serves as a blueprint for creating a specific protein, and having two functional copies ensures that a sufficient quantity of that protein is made. This concept is known as gene dosage, highlighting the importance of having the correct number of gene copies.
In haploinsufficiency, one of the two gene copies is either deleted, mutated, or otherwise rendered non-functional, meaning only one copy remains active. This single functional gene copy can only produce about half the normal amount of its corresponding protein. For some proteins, this reduced level is still enough for the body to function without noticeable problems. However, for certain genes, a 50% reduction in protein levels falls below a necessary threshold, leading to impaired cellular processes and, consequently, various health conditions.
Real-World Examples
Haploinsufficiency underlies several human genetic conditions, where the reduction in protein levels directly contributes to the observed symptoms.
Williams-Beuren Syndrome
This neurodevelopmental disorder is caused by the haploinsufficiency of multiple genes on chromosome 7. The deletion of genes, including ELN, is responsible for the syndrome’s features. Insufficient elastin, a protein providing elasticity to blood vessels, can lead to cardiovascular issues like supravalvular aortic stenosis, a narrowing above the aortic valve.
Neurofibromatosis Type 1 (NF1)
NF1 results from haploinsufficiency of the NF1 gene located on chromosome 17. The NF1 gene produces neurofibromin, a protein that acts as a tumor suppressor by regulating cell growth and division. When only one functional copy of NF1 is present, the reduced amount of neurofibromin leads to an increased risk of tumor formation, particularly benign tumors called neurofibromas, along nerve pathways, as well as characteristic skin pigmentation changes.
Cri-du-chat Syndrome
Named for the distinctive cat-like cry of affected infants, Cri-du-chat syndrome is caused by a deletion on the short arm of chromosome 5. This deletion results in the haploinsufficiency of several genes in that region. The loss of these genes contributes to intellectual disability, delayed development, and distinctive facial features. The severity of the symptoms can vary depending on the size and location of the deleted segment, which affects how many genes are impacted and the extent of protein reduction.
How It Differs From Other Genetic Conditions
Haploinsufficiency stands apart from other common genetic inheritance patterns, such as dominant and recessive traits, by the nature of the genetic defect.
In many dominant conditions, the presence of a single altered gene copy leads to a harmful or abnormal protein product that interferes with normal cellular function, often called a dominant negative effect. This faulty protein actively disrupts processes, even in the presence of a normal protein produced by the unaffected gene copy.
Conversely, in recessive conditions, an individual needs to inherit two non-functional copies of a gene, one from each parent, for the condition to manifest. In these cases, having one functional gene copy is sufficient to produce enough normal protein to prevent symptoms.
Haploinsufficiency is distinct because the problem is not a faulty protein, nor is it the requirement for two non-functional copies. Instead, the core issue is simply an insufficient quantity of a perfectly normal protein. The remaining single functional gene copy cannot produce enough of the necessary protein to reach the threshold required for normal physiological processes, leading to the manifestation of the genetic condition.