GNPTAB Gene, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
N-acetylglucosamine-1-phosphate transferase, alpha and beta subunits (GNPTAB)-related mucolipidoses are progressive lysosomal storage diseases traditionally classified as mucolipidosis II and mucolipidosis III based upon their severity and disease onset. These conditions have substantial clinical overlap and mutation testing can aid the diagnosis.
Mucolipidosis II alpha/beta (ML II alpha/beta or I-cell disease) is a progressive inborn error of metabolism with clinical onset at birth and fatal outcome most often in early childhood. Postnatal growth is limited and often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and hip dislocation. There is often cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death.
Mucolipidosis III alpha/beta (ML III alpha/beta or pseudo-Hurler polydystrophy) is a slowly progressive disorder with clinical onset at approximately 3 years of age. It is characterized by a slow growth rate and subnormal stature; radiographic evidence of mild to moderate dysostosis multiplex; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. If present, organomegaly is mild. Pain from osteoporosis that is clinically and radiologically apparent in childhood becomes more severe from adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood.
ML II/ML III alpha/beta are inherited in an autosomal recessive manner. Both disorders have been reported from nearly all parts of the world and the overall carrier rate ranges between 1 in 158 and 1 in 316.
GNPTAB is the gene in which mutations are most often known to cause ML II/ML III alpha/beta. Bidirectional sequencing of the entire GNPTAB coding region detects 2 disease-causing mutations in more than 95% of individuals with ML II/MLIII alpha/beta. This gene encodes 2 of 3 subunits (alpha/beta) of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. In the absence of this enzyme, a mannose 6-phosphate (M6P) recognition marker is not added to lysosomal hydrolases and other glycoproteins. This leads to disruption of acid hydrolases transport to the lysosome. Formation of the M6P recognition marker on lysosomal hydrolases is significantly reduced in ML III alpha/beta, and nearly or totally absent in ML II alpha/beta.
To confirm or establish the diagnosis in a proband requires a combination of clinical evaluation and laboratory testing. The use of the following diagnostic testing is recommended: Identification of characteristic clinical and radiographic findings, assay of oligosaccharides in urine, assay of several acid hydrolases in plasma, sequence analysis of GNPTAB. The activity of nearly all lysosomal hydrolases in plasma and other body fluids is higher in individuals affected with ML II alpha/beta (5- to 20-fold ) and ML III alpha/beta (up to 10-fold) than in normal controls. ML II/ML III alpha/beta is diagnosed by assay of N-acetylglucosamine-1-phosphotransferase in skin fibroblasts. Demonstration of nearly complete inactivity (<1%) of the enzyme confirms the diagnosis of ML II alpha/beta, whereas significant deficiency (1%-10% of normal) of this enzyme is suggestive of the diagnosis of ML III alpha/beta. Urinary excretion of oligosaccharides is often excessive. Prior to molecular analysis, the delineation of ML II alpha/beta from ML III alpha/beta depended solely on clinical criteria including age of onset, rate of progression, and overall severity.
Molecular genetic studies reveal a genotype-phenotype correlation supporting the clinical distinction between ML II alpha/beta and ML III alpha/beta. Mutations that completely inactivate the phosphotransferase consistently result in ML II alpha/beta irrespective of their location within the gene. Mutations with less adverse effect on this enzyme activity usually result in ML III alpha/beta or occasionally in intermediate phenotypes.(1,2)
Molecular diagnosis or carrier status of mucolipidosis II alpha/beta and mucolipidosis III alpha/beta in conjunction with identification of characteristic clinical, radiographic, and biochemical findings when familial mutations have been previously identified, and genetic counseling for family members
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who have a diagnosis of mucolipidoses II/III alpha/beta may have a mutation that is unidentifiable by this method (eg, large deletion/duplication, promoter mutations, deep intronic alterations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of mucolipidoses II/III alpha/beta. For carrier testing, it is important to first document the presence of GNPTAB mutations in an affected family member.
Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
Bone marrow transplants from allogenic donors will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Kudo M, Brem MS, Canfield WM: Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha/beta-subunits precursor gene. Am J Hum Genet 2006;78:451-463
2. Cathey SS, Leroy JG, Wood T, et al: Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet 2010;47:38-48