Abstract
BackgroundMucolipidosis II (ML II; I-cell disease) is caused by a deficiency of N-acetylglucosamine-1-phosphotransferase (GNPTAB; EC 2.7.8.17), which leads to a failure to internalize acid hydrolases into lysosomes for proper catabolism of various substances. This is an autosomal recessive lysosomal storage disease and causes severe progressive neuropathy and oculoskeletal dysfunction in humans (OMIM 252500). A naturally occurring disease model has been reported in juvenile domestic cats (OMIA 001248–9685) with clinical signs similar to human patients. We investigated the molecular genetic basis of ML II in a colony of affected cats by sequencing the coding and regulatory regions of GNPTAB from affected and clinically healthy related and unrelated domestic cats and compared the sequences to the published feline genome sequence (NCBI-RefSeq accession no. XM_003989173.4, Gene ID: 101100231).ResultsAll affected cats were homozygous for a single base substitution (c.2644C > T) in exon 13 of GNPTAB. This variant results in a premature stop codon (p.Gln882*) which predicts severe truncation and complete dysfunction of the GNPTAB enzyme. About 140 GNPTAB variants have been described in human ML II patients, with 41.3% nonsense/missense mutations, nine occurring in the same gene region as in this feline model. Restriction fragment length polymorphism and allelic discrimination real-time polymerase chain reaction assays accurately differentiated between clear, asymptomatic carriers and homozygous affected cats.ConclusionMolecular genetic characterization advances this large animal model of ML II for use to further define the pathophysiology of the disease and evaluate novel therapeutic approaches for this fatal lysosomal storage disease in humans.
Highlights
Mucolipidosis mucolipidosis II (II) (ML II; I-cell disease) is caused by a deficiency of N-acetylglucosamine-1-phosphotransferase (GNPTAB; EC 2.7.8.17), which leads to a failure to internalize acid hydrolases into lysosomes for proper catabolism of various substances
Mucolipidosis II (ML II, Ophthalmologic aOnline Mendelian Inheritance in Man (OMIM) 252500) is a hereditary lysosomal storage disease caused by the deficiency of N-acetylglucosamine-1-Phosphotransferase (GNPTAB, EC 2.7.8.17, previously known as GNPTA)
100 unrelated domestic short-hair (DSH) cats from the local Pennsylvania region did not have the mutant GNPTAB allele, and no other naturally occurring cases of ML II have been reported since the original kitten. This enzymatic and molecular genetic study of a related group of DSH cats clinically affected with ML II identifies the genetic defect causative of ML II to be a single nonsense variant in GNPTAB
Summary
Mucolipidosis II (ML II; I-cell disease) is caused by a deficiency of N-acetylglucosamine-1-phosphotransferase (GNPTAB; EC 2.7.8.17), which leads to a failure to internalize acid hydrolases into lysosomes for proper catabolism of various substances. This is an autosomal recessive lysosomal storage disease and causes severe progressive neuropathy and oculoskeletal dysfunction in humans (OMIM 252500). Mucolipidosis II (ML II, OMIM 252500) is a hereditary lysosomal storage disease caused by the deficiency of N-acetylglucosamine-1-Phosphotransferase (GNPTAB, EC 2.7.8.17, previously known as GNPTA) This enzyme is a heterohexamer composed of three homodimers: alpha (α), beta (β) and gamma (γ) in a molar ratio of 2:2:2. It is characterized by later onset (childhood) and slower progression
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