The PIG-L gene provides instructions for building an enzyme that is active in cells throughout the body. This gene is part of the “PIG” family, which participates in a fundamental cellular process. The enzyme’s work is part of a multi-step assembly line inside the cell, creating structures necessary for cell function and communication. Without its proper function, various cellular activities can be disrupted.
The Cellular Function of the PIG-L Gene
The PIG-L gene provides instructions for an enzyme involved in constructing glycosylphosphatidylinositol (GPI) anchors. GPI anchors are molecular tethers that attach over 150 different proteins to the outer surface of the cell membrane. GPI anchor production is a multi-step process in the endoplasmic reticulum, and the PIG-L enzyme is responsible for the second step.
The PIG-L enzyme performs a reaction known as de-N-acetylation. It removes an acetyl group from a precursor molecule, N-acetylglucosaminyl-phosphatidylinositol (GlcNAc-PI). This modification allows the GPI anchor assembly to continue. Once fully assembled, the GPI anchor is transferred to a protein, linking it to the cell’s exterior.
These anchored proteins function as receptors, enzymes, and adhesion molecules that allow cells to interact with their environment and communicate. This cell-to-cell signaling and adhesion is fundamental for the proper formation and function of tissues and organs during development and throughout life.
Syndromes Caused by PIG-L Mutations
Mutations in the PIG-L gene that prevent it from functioning correctly impair the production of GPI anchors. This leads to inherited GPI deficiencies (IGDs). The two primary syndromes are CHIME syndrome and a form of Mabry syndrome, also known as Hyperphosphatasia with Mental Retardation Syndrome (HPMRS). They are considered to be on a spectrum of the same underlying problem.
CHIME syndrome is an extremely rare disorder named as an acronym for its characteristic features:
- Colobomas (gaps in the structures of the eye)
- Congenital heart defects
- Ichthyosiform dermatosis (a specific type of scaly skin condition)
- Intellectual disability
- Ear anomalies
The skin rash is often migratory, appearing shortly after birth. Individuals may also have distinctive facial features and feeding difficulties.
Mabry syndrome (HPMRS) is characterized by significant developmental delay and a persistently elevated level of an enzyme in the blood called alkaline phosphatase (ALP). Both syndromes can involve intellectual disability and difficult-to-control seizures. However, individuals with Mabry syndrome do not have the characteristic eye, heart, or skin issues seen in CHIME. The specific PIG-L mutation can influence which syndrome develops.
Genetic Inheritance and Diagnosis
PIG-L gene disorders are inherited in an autosomal recessive pattern. An individual must inherit two non-working copies of the gene—one from each parent—to be affected. The parents are carriers, having one functional and one non-working copy. One functional copy is enough to prevent the disorder, but they can pass the non-working copy to their children.
The diagnostic process begins with a clinical evaluation of the patient’s symptoms, which point toward either CHIME or Mabry syndrome. Suspicion is then confirmed through molecular genetic testing. This involves whole-exome sequencing to find the specific mutations in the PIG-L gene responsible for the condition.
Elevated serum alkaline phosphatase is a useful biochemical marker that helps guide a diagnosis of Mabry syndrome. In some cases of CHIME syndrome, a common missense mutation is found on one copy of the gene, while the other copy has a more significant error, such as a large deletion.
Symptom Management and Care
There is no cure for the underlying genetic defect in PIG-L related syndromes. Medical care focuses on managing symptoms and supporting the individual’s development and quality of life. This requires a coordinated, multidisciplinary team of specialists to address the wide range of health issues.
For CHIME syndrome, this team often includes a cardiologist for heart defects and an ophthalmologist for vision problems. A dermatologist helps manage the chronic skin rash. Neurologists are involved in managing the difficult-to-control seizures common to both syndromes.
Developmental support is a central component of care for all affected individuals, utilizing physical, occupational, and speech therapies. Regular monitoring by the team is necessary to manage complications like feeding difficulties, hearing loss, or behavioral challenges. This ensures care is adapted to the person’s evolving needs.