Quaternary diagnostics scheme for mucolipidosis II and detection of novel mutation in GNPTAB gene

Mona L Essawi,Ekram M Fateen,Hanan A Atia,Noura R Eissa,Eman H Aboul-Ezz,Mona M Ibrahim,Heba A Hassan,Samia A Temtamy

doi:10.1186/s43141-021-00204-4

Abstract

BackgroundMucolipidosis II (ML II α/β) is an inherited lysosomal storage disorder caused by deficiency of GlcNAc-phosphotransferase enzyme and results in mis-targeting of multiple lysosomal enzymes. Affected patients are characterized by skeletal deformities and developmental delay. Homozygous or compound heterozygous mutations in GNPTAB gene are associated with the clinical presentation. This is the first study to characterize the underlying genetics of ML among a cohort of Egyptian patients. ML II diagnosis established by clinical assessment, biochemical evaluation of enzymes, electron microscopy examination of gingival inclusion bodies, and molecular study of GNPTAB gene using targeted next-generation sequencing panel in 8 patients form 8 unrelated Egyptian families. ResultsSequencing revealed 3 mutations in GNPTAB gene; 1 novel frame-shift mutation in exon 19 (c.3488_3488delC) and 2 previously reported mutations (c.1759C>T in exon 13 and c.3503_3504delTC in exon 19). All patients were homozygous for their corresponding mutations and the parents were consanguineous. ConclusionsAccording to the established quaternary diagnostic scheme, ML II was the final diagnosis in eight patients. The most common mutation was the frame shift c.3503_3504delTC mutation, found in 5 patients and associated with a severe phenotype.

Highlights

Mucolipidosis Mucolipidosis type II (II) (ML II α/β) is an inherited lysosomal storage disorder caused by deficiency of GlcNAcphosphotransferase enzyme and results in mis-targeting of multiple lysosomal enzymes
Two patients deceased before completing their clinical assessment; ML was suspected according to the biochemical and electron microscopy (E.M.) findings
This study identifies the first GNPTAB mutations in eight Egyptian patients with ML II

Summary

Introduction

Mucolipidosis II (ML II α/β) is an inherited lysosomal storage disorder caused by deficiency of GlcNAcphosphotransferase enzyme and results in mis-targeting of multiple lysosomal enzymes. Homozygous or compound heterozygous mutations in GNPTAB gene are associated with the clinical presentation This is the first study to characterize the underlying genetics of ML among a cohort of Egyptian patients. ML II α/β is caused by deficiency of the uridine diphosphate (UDP)-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase; EC 2.7.8.17) [12, 16]. This membrane-bound enzyme is responsible for the initial synthesis step of Mannose-6-Phosphate (M6P). Without M6P, newly synthesized lysosomal hydrolases processing and packaging are impaired and are misdirected and secreted They are rare genetically related inherited disorders of lysosomal metabolism. Their combined frequency is about 1: 422,000 live births. In the young founder population of the north-eastern region of Quebec [Saguenay–Lac-Saint-Jean (SLSJ)], ML II prevalence reached of 1/ 6184 at birth with an estimated carrier rate of 1/39 [18]

Methods

Results

Discussion

Conclusion