FAM126A

FAM126A, also known as HYCC1, encodes the protein hyccin—an essential component for myelin formation and phosphoinositide signaling in the nervous system. 

Mutations in this gene are most notably linked to hypomyelinating leukodystrophy with congenital cataracts (HCC) while emerging research suggests additional roles in cancer biology and systemic development.

What is FAM126A (Family with Sequence Similarity 126 Member A)?

FAM126A, also called HYCC1 (hyccin PI4KA lipid kinase complex subunit 1), is a gene located on chromosome 7p15.3 that encodes a protein called hyccin. This protein plays an important role in building and maintaining the myelin sheath, which insulates nerve fibers and ensures efficient nerve signal transmission.

Hyccin is also involved in key lipid signaling pathways that support nerve development and function.

Hyccin is also expressed in the eye lens, heart, and kidneys, although its specific role in these tissues has not yet been clearly defined.

Awareness of its multiple aliases (HYCC1, HLD5, DRCTNNB1A) is important for test ordering and interpretation.

FAM126A: Gene and Protein Characteristics

Gene Location: Chromosome 7p15.3

Protein Name: Hyccin

Protein Function:

• Myelin Formation and Maintenance: FAM126A is essential for forming healthy myelin in both the central and peripheral nervous systems.
• Lipid Signaling: Hyccin is part of the PI4KIIIα (PI4KA) complex, helping to make phosphatidylinositol 4-phosphate (PI4P), a key lipid for cell membrane identity and signaling.
• Structural Role: FAM126A binds directly to TTC7B and stabilizes the PI4KA complex at the plasma membrane, enhancing its enzymatic activity and enabling proper nerve development.

FAM126A and Associated Disorders

Mutations in FAM126A are linked to:

Hypomyelinating Leukodystrophy 8 (HLD8) / Hypomyelination and Congenital Cataract (HCC)

Hypomyelination and Congenital Cataract (HCC) is a rare autosomal recessive neurological disorder caused by mutations in the FAM126A gene. 

It is characterized by impaired myelin formation (hypomyelination) in the central nervous system, and bilateral congenital cataracts present at birth. Affected individuals typically appear developmentally normal during the first year of life, but developmental delays and motor regression emerge around age one.

Key features include delayed or abnormal myelination on brain MRI, early-onset motor dysfunction (spasticity, ataxia, and peripheral neuropathy), mild to moderate intellectual disability, and dysarthria. 

Progressive muscle weakness, leg atrophy, and scoliosis may lead to wheelchair dependence over time. 

HCC is part of the leukoencephalopathy spectrum, which involves white matter abnormalities due to disrupted myelin production.

FAM126A and Cancer

FAM126A is often overactive in pancreatic cancer, where it helps cancer cells grow and spread by activating the PI3K/AKT pathway and triggering changes like EMT. This makes FAM126A a potential target for cancer treatment.

FAM126A may also have clinical relevance in colorectal cancer. One research paper explains that, in some colorectal cancers, the FAM126A gene gets turned off, forcing the cancer cells to rely on a similar gene called FAM126B—making FAM126B a possible target for new cancer treatments.

Who Should Get FAM126A Genetic Testing?

The following groups of people may consider FAM126A testing:

Individuals with Suspected HLD8 or HCC

Genetic testing for FAM126A is recommended for individuals showing signs consistent with hypomyelinating leukodystrophy type 8 (HLD8) or hypomyelination and congenital cataract syndrome (HCC). 

Clinical features often include early-onset neurological symptoms in infancy or childhood, such as developmental delay and motor regression. 

Brain MRI findings typically reveal diffuse hypomyelination, and some individuals may also present with congenital cataracts. 

Testing can confirm a diagnosis and guide care planning.

Family Members of Affected Individuals

Carrier testing may be appropriate for parents or relatives of individuals diagnosed with a FAM126A-related disorder. 

Identifying carriers helps assess reproductive risk and enables informed family planning decisions. It also offers insight into whether siblings or other relatives may be affected or at risk.

For Differential Diagnosis of Leukodystrophies

FAM126A testing can help distinguish HLD8 from other leukodystrophies with overlapping features. It may be used alongside genetic testing for conditions related to other genetic mutations when evaluating unexplained hypomyelination.

With Genetic Counseling

Because FAM126A-related conditions are inherited and often progressive, pre- and post-test genetic counseling is essential. 

Counseling helps patients and families understand inheritance patterns, the clinical significance of test results, and potential next steps for medical management or family planning.

What Do Specific FAM126A Mutations Mean?

Various genotypic mutations may occur, which may present with different phenotypes:

Complete Loss-of-Function Mutations: (e.g., deletions, premature stop codons)

Complete loss-of-function mutations lead to severe forms of HLD8 with profound neurological dysfunction.

Leu53Pro (L53P) Missense Mutation

The L53P missense mutation allows for partial hyccin production and is associated with a milder disease course.

What Does the Absence of a FAM126A Mutation Mean?

A negative test result does not rule out all genetic causes of leukodystrophy or hypomyelination.

Consider broader genetic panels or testing for other leukodystrophy-associated genes if suspicion remains high.

Neuroimaging and Neuropathology Findings

MRI Hallmarks

Findings on brain MRI typically include:

• Diffuse white matter hypomyelination
• Corpus callosum thinning
• Cerebellar and brainstem involvement
• Evolving gliosis and white matter atrophy

Sural Nerve Biopsy

Sural nerve biopsy may demonstrate severe hypomyelination, decreased nerve fiber density, and in some cases, onion bulb formations.

Test Procedure and Interpretation

Testing for FAM126A is often performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for FAM126A genetic testing are considered to be without mutations that can alter the activity of the FAM126A proteins.

Clinical Implications of Positive FAM126A Mutations

The clinical implications of a positive FAM126A mutation test result will vary by individual, although FAM126A mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various symptoms affecting neurological function and/or vision.

Patients or practitioners with questions about the clinical implications of FAM126A mutations should seek further assessment with a genetic counselor or expert. 

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