Mucolipidosis III is genetically heterogeneous.

Abstract

Mucolipidosis m (ML HI), or pseudo-Hurler polydystrophy, is an inherited childhood disorder characterized biochemically by low activities and abnormal electrophoretic patterns of multiple lysosomal enzymes in fibroblasts. The primary deficiency of ML Im has been proposed to be in UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-l-phosphotransferase. However, variation in this enzyme and in other biochemical properties of different ML mI lines has been observed. Therefore, we investigated genetic heterogeneity within the disorder by complementation analysis. Heterokaryon cell fractions were generated by fusing together ML m fibroblast lines. When pairs of cells complemented, correction of lysosomal enzyme activities and electrophoretic patterns was observed. Twelve fibroblast lines from 10 sibships were analyzed and three distinct complementation groups were characterized. One complementation group represents the classical ML HI disorder. A single cell line identifies a second complementation group. The cell lines comprising a third complementation group have a number of biochemical characteristics different from classical ML HI and may represent a genetically distinct disorder.

Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC)

“…The genetic relationships between the multiple variants of MLII and MLIII are complex and have been difficult to understand in the absence of information about the gene(s) involved (14)(15)(16)35). This study demonstrates the MLIII(C) phenotype can result from a mutation in the GlcNAc-phosphotransferase γ subunit.…”

“…Heterokaryon analysis has been used to divide MLIII into 3 distinct complementation groups (15,16). Complementation group A (classic MLIII) is characterized by moderately decreased GlcNAc-phosphotransferase activity measured on all substrates.…”

Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype–phenotype correlation

“…6 A series of genetic-complementation studies have shown heterogeneity in ML III and the genetic relationship between ML II and III. [7][8][9] Mutations in GNPTAB cause both the severe type of ML (ML II alpha/beta, ML II, I-cell disease (MIM 252500)) and the attenuated type of ML (ML III alpha/beta, ML IIIA, PseudoHurler polydystrophy (MIM 252600)). [10][11][12] Mutations in GNPTG cause the attenuated type of ML (ML III gamma, ML IIIC, ML III variant (MIM 252605)).…”

Trafficking of lysosomal enzymes in normal and disease states.

“…Fibroblasts from patients with ML-II have extremely low or undetectable enzyme levels, whereas fibroblasts from patients with ML-III have some residual phosphorylating activity consistent with their milder clinical course (38)(39)(40)(41)(42). Cell fusion experiments have defined complementation groups among various ML-II and ML-III fibroblast lines (69,70). The ML III lines have been placed into two distinct complementation groups, with the possible existence of a third (69).…”