Mucolipidosis type IV (Mucolipidosis type IV) - Gen MCOLN1
Mucolipidosis IV is an inherited disease characterized by developmental delay and the progressive deterioration of vision. The severe form of the disease is called mucolipidoses typical type IV and mild, atypical mucolipidoses type IV.
Approximately 95% of people with type IV mucolipidoses have the severe form. People with type IV manifest mucolipidoses typical moderate to severe psychomotor retardation becomes evident, usually during the first year of life. As a result, affected individuals manifest intellectual disability, limitation or absence of speech, difficulty chewing and swallowing, hypotonia, spasticity and problems controlling hand movements. Most people with typically are unable to walk independently. In about 15% of those affected, psychomotor problems worsen over time. Vision may be normal at birth in people with the typical form, but it deteriorates progressively during the first decade of life, as a result of corneal opacification and the progressive decomposition of the retina. Other manifestations typically include achlorhydria, resulting in unusually high concentrations of gastrin in the blood, and anemia. Usually, people with the severe form survive into adulthood, although they may have a shorter life.
About 5% of those affected have the atypical form of type IV mucolipidoses. These individuals often have mild psychomotor retardation and can develop the ability to walk. People with atypical tend to have milder than those with the severe form of the disease ocular abnormalities. Achlorhydria may also occur in individuals mildly affected.
Both typically as atypical form of the disease they are due to mutations in the gene MCOLN1 (mucolipin 1), located on the short arm of chromosome 19 (19p13.2). This gene encodes a protein called mucolipin-1 found in the lysosomal membranes and endosomal compartments inside the cell digest and recycle the materials. Although its function is not completely understood, mucolipin-1 plays a role in the transport of lipids and proteins between the lysosomes and endosomes. Mucolipin-1 acts as a channel, allowing the cations penetrations lysosomal membranes and endosomes. However, it is unclear what cations are allowed to flow through this channel. Mucolipin-1 appears to be important for the development and maintenance of the brain and retina. Furthermore, it is likely that this protein is critical for normal functioning of cells produced in the stomach digestive acids.
They have been described at least 22 MCOLN1 gene mutations in people with mucolipidosis type IV. Most of these mutations result in the synthesis of a nonfunctional or inhibited encoding any protein. Two particular mutations in the gene MCOLN1, are responsible for almost all cases of type IV mucolipidoses in people with Ashkenazi Jewish ancestry. The most common mutation, 406-2A> G, change a single nucleotide in intron 3 gene. This mutation, termed a splice site mutation introduces a premature stop signal in coding mucolipin-1. The other mutation, 511_6943del, removes a large amount of DNA near the beginning of MCOLN1 gene. Both of these mutations lead to the synthesis of an abnormally short, nonfunctional protein. The absence of functional mucolipin-1 alters the transport of lipids and proteins, causing these substances accumulate in the lysosomes. It is still unclear how mutations in the gene cause MCOLN1 psychomotor retardation, progressive vision loss and achlorhydria in people with mucolipidosis type IV.
This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with mucolipidosis type IV, by complete PCR amplification of exons MCOLN1 gene, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).