Next Generation Sequencing identifies mutations in GNPTG gene as a cause of familial form of scleroderma-like disease

Zrhidri, Abdelali; Amasdl, Saadia; Lyahyai, Jaber; Elouardi, Hanane; Chkirate, B.; Raymond, Laure; Egéa, Grégory; Taoudi, Mohamed; Mouatassim, Said El; Sefiani, Abdelaziz

doi:10.1186/s12969-017-0200-2

Cited by 4 publications

(3 citation statements)

References 23 publications

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“…For detection of the GNPTAB and GNPTG variants Sanger sequencing was predominantly applied. However, next‐generation sequencing technologies, for example, whole‐exome sequencing followed by validation of the mutation by Sanger sequencing, was also used for variant identification in a number of studies (Costain et al, ; Hashemi‐Gorji, Ghafouri‐Fard, Salehpour, Yassaee, & Miryounesi, ; Khan, Hussain, Sher, Zubaida, & Naeem, ; Retterer et al, ; Schrader et al, ; Soden et al, ; Sperb‐Ludwig et al, ; Zrhidri et al, ; Fernández‐Marmiesse et al, ; Yang et al, ). All novel GNPTAB and GNPTG mutations were identified by the authors of this study in families from Brazil, Chile, Germany, Italy, Portugal, the Netherlands, Turkey, United Kingdom, and United States.…”

Section: Gnptab and Gnptg Mutationsmentioning

confidence: 99%

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

et al. 2019

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Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/β‐precursor and the γ‐subunit of N‐acetylglucosamine (GlcNAc)‐1‐phosphotransferase, respectively, the key enzyme for the generation of mannose 6‐phosphate targeting signals on lysosomal enzymes. Defective GlcNAc‐1‐phosphotransferase results in missorting of lysosomal enzymes and accumulation of non‐degradable macromolecules in lysosomes, strongly impairing cellular function. MLII‐affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc‐1‐phosphotransferase, but also helped to define genotype‐phenotype correlations to predict the clinical outcome in patients.

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Section: Gnptab and Gnptg Mutationsmentioning

confidence: 99%

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

et al. 2019

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“…The skin may become thickened with time. Recently scleroderma-like symptoms were described in MLIII patients (28). Because skeletal dysplasia is the most prominent clinical complication in the MLIII disease, patients can survive into adulthood (33).…”

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confidence: 99%

Lysosomal Proteome and Secretome Analysis Identifies Missorted Enzymes and Their Nondegraded Substrates in Mucolipidosis III Mouse Cells

Lorenzo

Velho

Winter

et al. 2018

Molecular & Cellular Proteomics

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Targeting of soluble lysosomal enzymes requires mannose 6-phosphate (M6P) signals whose formation is initiated by the hexameric N-acetylglucosamine (GlcNAc)-1-phosphotransferase complex (αβγ). Upon proteolytic cleavage by site-1 protease, the α/β-subunit precursor is catalytically activated but the functions of γ-subunits (Gnptg) in M6P modification of lysosomal enzymes are unknown. To investigate this, we analyzed the expression in mouse tissues, primary cultured cells, and in reporter mice , and found high amounts in the brain, eye, kidney, femur, vertebra and fibroblasts. Consecutively we performed comprehensive quantitative lysosomal proteome and M6P secretome analysis in fibroblasts of wild-type and mice mimicking the lysosomal storage disorder mucolipidosis III. Although the cleavage of the α/β-precursor was not affected by deficiency, the GlcNAc-1-phosphotransferase activity was significantly reduced. We purified lysosomes and identified 29 soluble lysosomal proteins by SILAC-based mass spectrometry exhibiting differential abundance in fibroblasts which was confirmed by Western blotting and enzymatic activity analysis for selected proteins. A subset of these lysosomal enzymes show also reduced M6P modifications, fail to reach lysosomes and are secreted, among them α-l-fucosidase and arylsulfatase B. Low levels of these enzymes correlate with the accumulation of non-degraded fucose-containing glycostructures and sulfated glycosaminoglycans in lysosomes. Incubation of fibroblasts with arylsulfatase B partially rescued glycosaminoglycan storage. Combinatorial treatments with other here identified missorted enzymes of this degradation pathway might further correct glycosaminoglycan accumulation and will provide a useful basis to reveal mechanisms of selective, Gnptg-dependent formation of M6P residues on lysosomal proteins.

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“…With great interest, we read Zrhidri et al’s paper [ 1 ] which reports compound heterozygous mutations in exon 4 and 9 of the GNPTG gene, in a familial scleroderma-like disease. This novel finding represents an important addition to the family of genetic mutations previously associated with multisystemic fibrosis and scleroderma-like diseases in literature.…”

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confidence: 99%