Microphthalmia with linear skin defects syndrome (MLS syndrome) is a genetic condition that affects the eyes and skin. It is mainly found in females and is characterized by small or poorly developed eyes (microphthalmia) and characteristic linear skin markings on the head and neck. The signs and symptoms of this condition may include abnormalities of the brain, heart, and genitourinary system. Other symptoms may include short stature, developmental delay, and finger and toenails that do not grow normally (nail dystrophy). MLS syndrome is typically caused by either a deletion of certain genetic material on the p (short) arm of the X chromosome or by a mutation in the HCCS gene. In some cases, it may be caused by mutations in the COX7B and NDUFB11 genes, (also located on the X chromosome). According to the mutated gene, the disease may be classified in three subtypes. This condition is inherited in an X-linked manner and is thought to result in serious early developmental concerns in males, leading to almost no males with this condition surviving to delivery. Although there is no specific treatment or cure for MLS syndrome, there may be ways to manage the symptoms. A team of doctors is often needed to figure out the treatment options based on each person’s symptoms.

• Poor development of the clear layer that covers the front of the eye (sclerocornea)
• Cysts in the cavity of the skull where the eye is located (orbital cysts)
• Congenitalglaucoma

• Brain malformations
• Developmental delay
• Intellectual disability
• Short stature
• An abnormal opening in the diaphragm (diaphragmatic hernia)
• Finger and toenails that do not grow normally (nail dystrophy)
• A small pit in the outside part of the ear (preauricular pits)
• Hearing loss
• Heart defects
• Abnormalities in the development of the genitals and urinary tract
• A missing or blocked opening in the anus

Normal Function

The HCCS gene carries instructions for producing an enzyme called holocytochrome c-type synthase. This enzyme is active in many tissues of the body and is found in the mitochondria, the energy-producing centers within cells.

Within the mitochondria, the holocytochrome c-type synthase enzyme helps produce a molecule called cytochrome c. Specifically, holocytochrome c-type synthase is involved in a reaction that adds an iron-containing molecule called heme to make mature cytochrome c, also called holocytochrome c, from a precursor form called apocytochrome c.

Cytochrome c is involved in a process called oxidative phosphorylation, by which mitochondria generate adenosine triphosphate (ATP), the cell's main energy source. It also plays a role in the self-destruction of cells (apoptosis).

Health Conditions Related to Genetic Changes

Microphthalmia with linear skin defects syndrome

At least three HCCS gene mutations have been identified in individuals with microphthalmia with linear skin defects syndrome. Deletions of genetic material that include the HCCS gene have also been identified in affected individuals. HCCS gene mutations result in a holocytochrome c-type synthase enzyme that cannot perform its function. A deletion of genetic material that includes the HCCS gene prevents the production of the enzyme from that copy of the gene. This loss of functional holocytochrome c-type synthase enzyme can damage cells by impairing their ability to generate energy. In addition, without sufficient holocytochrome c-type synthase enzyme, the damaged cells may not be able to undergo apoptosis. These cells may instead die in a process called necrosis that causes inflammation and damages neighboring cells. During early development this spreading cell damage may lead to the eye and skin abnormalities characteristic of microphthalmia with linear skin defects syndrome.

Coloboma

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Other Names for This Gene

• CCHL
• CCHL_HUMAN
• DKFZp779I1858
• holocytochrome c synthase (cytochrome c heme-lyase)
• MCOPS7

Genomic Location

Normal Function

The HLCS gene provides instructions for making an enzyme called holocarboxylase synthetase. This enzyme is important for the effective use of biotin, a B vitamin found in foods such as liver, egg yolks, and milk. In many of the body's tissues, holocarboxylase synthetase turns on (activates) enzymes called biotin-dependent carboxylases by attaching biotin to them. These carboxylases are involved in many critical cellular functions, including the production and breakdown of proteins, fats, and carbohydrates.

Holocarboxylase synthetase plays a role in regulating the activity (transcription) of genes. Transcription is the first step in the process of producing proteins. Specifically, the enzyme regulates genes that play a role in the transport and use of biotin in cells. Biotin is needed for the normal function of many tissues, including the brain, muscles, liver, and kidneys.

Health Conditions Related to Genetic Changes

Holocarboxylase synthetase deficiency

About 50 mutations in the HLCS gene have been identified in people with holocarboxylase synthetase deficiency, which is characterized by the body's inability to use biotin effectively. Affected infants often have difficulty feeding, breathing problems, a skin rash, hair loss (alopecia), and a lack of energy (lethargy). If left untreated, the disorder can lead to delayed development, seizures, and coma. These medical problems may be life-threatening in some cases.

Most of the HLCS gene mutations change a single protein building block (amino acid) in the holocarboxylase synthetase enzyme. Many of the known mutations occur in a region of the enzyme that binds to biotin. These genetic changes reduce the enzyme's ability to attach biotin to carboxylases. Without biotin, carboxylases remain inactive and are unable to process proteins, fats, and carbohydrates effectively. A lack of holocarboxylase synthetase activity may also alter the regulation of certain genes that are needed to transport and use biotin in cells. Researchers believe that these defects in enzyme function underlie the signs and symptoms of holocarboxylase synthetase deficiency.

Other Names for This Gene

• biotin apo-protein ligase
• biotin-protein ligase
• BPL1_HUMAN
• HCS
• holocarboxylase synthetase (biotin-(proprionyl-CoA-carboxylase (ATP-hydrolysing)) ligase)
• holocarboxylase synthetase (biotin-(proprionyl-Coenzyme A-carboxylase (ATP-hydrolysing)) ligase)

Genomic Location

X-linked, as related to genetics, refers to characteristics or traits that are influenced by genes on the X chromosome. Humans and most other mammals have two sex chromosomes, X and Y. Females have two X chromosomes in their cells, while males have one X and one Y. In the case of an X-linked disease, it is usually males that are affected because they have a single copy of the X chromosome that carries the disease-causing mutation. In females, the presence of a second, non-mutated copy may cause different, milder, or no symptoms of a sex-linked disorder.

X-Linked. The way X-linked traits may manifest differently in females and males can be due to more complex phenomena such as X-inactivation, and exactly how copies of the X chromosome a person has. A simple rule of thumb for most X-linked conditions is that females generally have a milder version of the condition compared to males.

Julie C. Sapp, Sc.M., C.G.C., Genetic Counselor, Precision Genomics Section