Haplossuficency and haploinsufficiency

Here I explain a concept that I believe is part of the core of genetics. Understanding what haploinsufficiency is, is like lighting a lamp in the dark, as it will open the door for you to understand complex concepts of genetics.

By Alfonso Prado-Cabrero, PhD

Human glucose transporter I

Researchers classify a gene as haplosufficient (HS) or haploinsufficient (HI) after learning from their experiments about:

1. Where is the gene active (in which organs or tissues).
2. The minimum level of work that each of these organs or tissues need from the gene.

Haplosufficiency

Haplosufficiency characterizes most genes in a diploid organism. In the organs where a HS gene works (brain, heart, etc.), it does not matter whether both alleles of the gene or only one of them is healthy and active (Fig 1). As you can see in Fig. 1, for HS genes the range of permissiveness in terms of required work is very loose, as 50% of work is still ok.

Figure 1. Gene A as an example of a haplosufficient gene (HS). This gene is active in brain, heart and liver. (A) A person with alleles A*1 and A*2, both working correctly. In all organs where it is active, the minimum work required for this gene is 50 (arbitrary units), symbolised by the black triangles. As both alleles are healthy, their cumulative work is 100 (arbitrary units). Therefore, the work required of this gene is fulfilled in all the organs where it is active (organs filled in green). (B) In this person, one of the alleles does not work (allele A*3). Still, the work performed by the gene accounts for 50 arbitrary units (from allele A*1), which is the minimum rewuired for this gene for the correct functioning of all organs where it works (organs still filled in green).

 Haploinsufficiency

Haploinsufficiency characterizes a minority of genes in a diploid organism. What makes a gene HI is a tissue that needs this gene working beyond the activity of a single healthy allele. Therefore, the gene cannot meet the demands of this tissue if one of the alleles is damaged. This leads to a disease related to said gene in that tissue (Fig. 2).

Figure 2. Gene B as an example of a haploinsufficient (HI) gene. This gene is active in lungs, stomach and small intestine. (A) A person with the alleles B*1 and B*2, both operating properly. Therefore, the work performed by the products of these alleles exceeds the minimum work required for normal function in all the organs where it is active. (B) A person with the alleles B*1 and B*3, where B*3 is not active due to a mutation. As a result, the total activity of the gene in this person is produced only by the healthy allele. As the minimum work required for the gene B is 70 arbitrary units in the small intestine, its function is insufficient in this organ, causing a disease.

Haploinsufficiency and partial loss of function

Nevertheless, total loss of activity of an allele is unusual to happen. Instead, milder mutations, provoking partial loss of function in the allele, are more frequent, since these are less lethal and therefore are more likely transmitted to offspring.

Therefore, haploinsufficiency normally happens with just a subtle decrease in the activity of an allele in a tissue where near maximum capacity of work of that gene is required. We will see an example of this in the next section.

The GLUT1 gene is haploinsufficient

The glucose transporter GLUT1 (Fig. 3) is key in the transport of glucose from the bloodstream to the brain, where it is used to fuel cognitive function (Harik et al., 1988). It is well documented that a drop in the supply of glucose to the brain may lead to the development of GLUT1 deficiency syndrome (Harik et al., 1990). The most common symptoms of this syndrome, in different degrees of severity, are neurodevelopmental delay, epileptic encephalopathy, acquired microcephaly, ataxia, dystonia and spasticity (De Vivo et al., 1991).

Figure 3. Human GLUT1 protein

The brain requires a minimum of 75% of the total activity of GLUT1 to stay in the safe side. If the work level of GLUT1 falls to 60%, GLUT1 deficiency syndrome appears with mild symptoms. If the work level of GLUT1 drops to 50%, the clinical symptoms will be severe (Yang et al., 2011).

Red blood cells (erythrocytes) also use the GLUT1 protein. Nevertheless, these cells still work efficiently with only one allele of GLUT1. Why is this scenario different from the brain? A definitive reason to explain this is unknown. Nevertheless, a possible hypothesis is related to the fact that erythrocytes do not have DNA. Instead, the bone marrow loads erythrocytes with mRNAs for latter translation into proteins. Maybe this pre-load is enough for erythrocytes to thrive. Another possible hypothesis to explain this relates to the molecule transported by GLUT1 in erythrocytes. In these cells, GLUT1 does not transport glucose, but a similar molecule, vitamin C (Fig. 4). Maybe, lower uptake of vitamin C by erythrocytes is not as debastating as lower uptake of glucose for the brain. In any case, the example of Glut1 demonstrates the complexity of classifying each gene as HS or HI. 

Figure 4. Glucose (left) and Vitamin C (Right)

The GLUT2 gene is haplosufficient

The GLUT2 gene also encodes a glucose transporter. Nevertheless, researchers have classified this gene as  HS. GLUT2 is active in pancreatic beta cells, hepatocytes, enterocytes, and renal tubular cells. The disease that results from the failure of GLUT2 is known as Fanconi-Bickel syndrome (Santer et al., 1997), but this disease only manifests when the two GLUT2 alleles fail.

Why do the GLUT1 and GLUT2 genes, both dedicated to glucose transport, behave so differently concerning haplosufficiency? The key is that the role of introduced glucose is different.

In contrast to GLUT1, GLUT2 has a low affinity for glucose. This might be a negative attribute on a glucose transporter. However, it is an essential trait if the goal is to detect glucose in blood only when it is at a high concentration, as happens after a meal. This is what GLUT2 does in pancreatic beta cells. After GLUT2 mediates glucose entrance in pancreatic beta cells, this sugar triggers insulin release to the bloodstream. Insulin then reaches the rest of the body communicating that there is “plenty of glucose in the bloodstream, ready to be taken and used as fuel”. Imagine GLUT2 having high affinity for glucose: the result would be the body trying to capture inexistent glucose from the bloodstream…

In this scenario, it appears that when a GLUT2 allele does not work, the glucose introduced is still enough to trigger this insulin release in pancreatic beta cells. The reason

The inheritance pattern of diseases caused by Haploinsufficient genes is dominant

From the above, it follows that for an HI gene, a significant loss of activity in one allele causes disease. Therefore, diseases caused by HI genes follow a dominant inheritance pattern. In fact, mutations in HI genes are the main cause of dominant diseases.

How many HI genes there are in the human genome?

The quick answer to this question is that it is currently unknown how many HI genes exist in the human genome. Nevertheless, continuous research is making advancement in this field. In 2008, the group of M. A. Ragan collected in a review article the 299 genes for which there was evidence to classify them as HI (Dang et al., 2008).

In 2010, the group of M. E. Hurles (Huang et al., 2010) developed a bioinformatics tool with the characteristics of the 301 HI genes and the 1076 HS genes that were already known at that time. Next, they analyzed 12,443 well-known genes of the human genome not yet classified as either HS or HI. As a result, they assigned a probability of belonging to one or the other group. If we assume that the genes with a 90% probability of being HI in this study are definitely HI genes, then approximately 600 of the 12,443 genes investigated would fall into this category. Extrapolating this information to the 22,500 genes of the human genome, then approximately 1080 genes would probably be HI. This accounts for about 5% of the total genes of our genome.

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