Introduction

Autosomal recessive inheritance refers to a particular pattern of how a person can inherit a genetic trait from their parents. There are two different forms in which a single gene can exist in a person: the dominant form or the recessive form. The dominant and recessive forms of the genes usually result in different traits. Depending on how you inherited the gene, you can either inherit the dominant form of the gene from both your parents (homozygous dominant) or the recessive form from both your parents (homozygous recessive). In some cases, you can also inherit the dominant form of the gene from one parent and then the recessive form from your other parent (heterozygote). With autosomal recessive inheritance, you inherit the recessive form of the gene from both of your parents, as is the case with CARD9 deficiency.^1–4

This article will discuss gene inheritance and how it causes disease in CARD9 deficiency. The article will also provide more information on CARD9 deficiency.

A look into gene inheritance and CARD9 deficiency

A brief explanation of how gene inheritance works

Genes can loosely be defined as the codes that tell the cells in our bodies how to behave. In humans, a single gene occurs in two forms, the dominant and recessive forms. These versions of the same genes are referred to as alleles. Even though they are the same gene, the recessive and dominant forms of a gene may influence the cells differently. When a person inherits the dominant allele from both parents, the cell behaves according to what the dominant allele encodes. In cases where a person has only recessive alleles, the cell will be influenced by the recessive form of the gene. However, a person who inherits a dominant allele and a recessive allele is likely to exhibit the characteristics that are encoded by the dominant allele. This is because the dominant allele “dominates” over the recessive allele, which "recedes". This concept of dominant and recessive gene alleles is referred to as Mendelian genetics.

In a disease, the dominant and recessive alleles could be different in that one allele may encode for a disease, whilst the other allele could result in a healthy person. If the dominant gene encodes for a disease, people who are homozygous dominant or heterozygous for that gene will have that particular disease. Only people who are homozygous recessive will be healthy. Inversely, if the recessive allele is the cause of the disease, the disease will only manifest in people who are homozygous recessive. This is the case in CARD9 deficiency, whereby the gene allele that causes the disease is recessive. Diseases that are a result of the recessive allele are called autosomal recessive disorders. Where the disease-causing allele is recessive, and a person is heterozygous, that person is said to be a carrier of that particular disease. This is because the person has the potential to pass on the disease to their children if the other parent is also a carrier or is homozygous recessive.

The pathophysiology of CARD9 deficiency

CARD9 deficiency is a rare genetic disease that makes people more susceptible to fungal infections.^1,5 When a person is CARD9 deficient, it means that the person’s CARD9 (caspase recruitment domain-domain containing protein 9) gene is not fully functional. The CARD9 gene is what tells immune cells to produce the CARD9 protein. The CARD protein is involved in biochemical pathways that are used by cells to fight off fungal infections.^2,3,5,6

Therefore, people with CARD9 deficiency suffer from fungal infections that affect many organs in the body. What would normally be a fungal infection of the skin (dermatophytosis) in healthy people can become a more serious infection in people who have CARD9 deficiency. So instead of the infection remaining on the outer layer of the skin, it can penetrate deep into the skin, also affecting the nails and hair. This disease can also affect the mouth, lungs, lymph nodes, bones, brain and other parts of the body.^3,6 Some of the fungi that have most commonly been found to be associated with CARD9 deficiency are the fungi that cause ringworms and athlete’s foot.

Clinical manifestations of CARD9 deficiency

These are some of the symptoms that have been reported in CARD9 deficiency patients:²

• Headaches
• Fever
• Vomiting
• Mental instability
• Bone pain if the bones are also infected
• The eyes may also be infected by the fungi, leading to vision loss

Diagnosis of fungal infections and CARD9 deficiency

• Specimens are taken from the patient to test them for the presence of fungi
• Fungal infections can be confirmed through a physical examination by the doctor
• If fungal infections are recurrent with relapses even after treatment, the doctor may take the family history into consideration
• Medical imaging can also help to identify fungal infections that have reached the brain
• To confirm if a person is indeed CARD9-deficient, the CARD9 gene would have to be sequenced

Treatment of CARD9 deficiency

To treat CARD9 deficiency, anti-fungal treatments such as fluconazole and amphotericin B are administered.² There is also the prospect of using granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) to treat fungal infections in patients who are CARD9 deficient. CARD9-deficient patients who were infected with fungi were cured of their infection when GM-CSF or G-CSF were administered together with anti-fungal drugs.⁷ However, there are only a handful of patients who have been reported to be cured using GM-CSF and G-CSF therapy. GM-CSF and G-CSF are proteins of the immune system that enhance the production of more immune cells (white blood cells). These proteins are used to treat patients with a low number of immune cells, usually due to receiving anti-cancer chemotherapy and radiation treatment.⁸ 

FAQs

What does CARD9 do for the body?

CARD9 is a protein that is produced by the body. It serves as a signal that tells the bone marrow to produce more white blood cells.

What can be used to treat CARD9 deficiency?

CARD9 deficiency makes it more likely for someone to get severe fungal infections. In cases of fungal infections, anti-fungal treatment is administered.

How does autosomal recessive inheritance cause CARD9 deficiency?

If a person receives a CARD9 deficiency recessive allele from both their parents, they will become CARD9 deficient.

Summary

Autosomal recessive inheritance refers to when a person receives recessive alleles for a particular gene from both their parents. If the recessive allele is defective, the person inherits the medical condition that is specific to that gene. This is also the case in CARD9 deficiency. CARD9 is a gene that tells the body to make the CARD9 protein, which plays a role in fighting off fungal infections. In CARD9-deficient patients, the CARD9 protein that is produced is defective and unable to protect against fungal infections. As a result, affected persons get severe fungal infections that may also affect the brain and other internal organs. The standard treatment for CARD deficiency is to administer anti-fungal drugs as fungal infections emerge.