Genetic Testing of a Large Consanguineous Pakistani Family Affected with Mucolipidosis III Gamma Through Next-Generation Sequencing

Khan, Mahnoor; Hussain, Akhtar; Sher, Gulab; Zubaida, Bibi; Naeem, Muhammad

doi:10.1089/gtmb.2018.0123

Cited by 2 publications

(9 citation statements)

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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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“…Mucolipidosis type 3 gamma (MLIIIγ) is a rare, slowly progressive lysosomal storage disease reported for the first time by Maroteaux and Lamy in 1966. [1][2][3][4][5] It is inherited in an autosomal recessive (AR) manner. [1][2][3][4][5] Stiffness in the finger joints usually begins in early childhood, whereas short stature, scoliosis and skeletal deformities are observed as a result of large joint involvement with advancing age.…”

mentioning

confidence: 99%

“…[1][2][3][4][5] It is inherited in an autosomal recessive (AR) manner. [1][2][3][4][5] Stiffness in the finger joints usually begins in early childhood, whereas short stature, scoliosis and skeletal deformities are observed as a result of large joint involvement with advancing age. 5 N-acetyl glucosamine-1 phospotransferase (GlcNAc-PTase) enzyme is a 540-kDa weight heterohexameric polypeptide composed of 2α, 2β and 2γ subunits.…”

mentioning

confidence: 99%

“…5 N-acetyl glucosamine-1 phospotransferase (GlcNAc-PTase) enzyme is a 540-kDa weight heterohexameric polypeptide composed of 2α, 2β and 2γ subunits. [1][2][3][4][5][6][7][8][9] Membrane dependent enzyme precursors α2β2 subunits and γ2 subunits are combined and carried to the Golgi apparatus. 4 Here, the α2β2 subunits in the precursor enzyme complex are activated with cleavage by site-1 protease (S1P).…”

mentioning

confidence: 99%

“…4 The active enzyme plays an essential role in the transport of hydrolases to the lysosomes by modifying them with addition of mannose-6-phosphate (M6P) residues in the Golgi apparatus. [2][3][4][5][6] Hydrolases that cannot be modified with M6P as a result of GlcNAc-PTase enzyme deficiency cannot be transported to lysosomes. 1,4,6 Hence, non-digestible macromolecules accumulate in lysosomes, as granular intracytoplasmic inclusion bodies that can be seen microscopically.…”

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confidence: 99%

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The rare reason of pain in hip girdle: Mucolipidosis type 3 gamma

Kolkiran¹,

Karaosmanoğlu²,

Taşkıran³

et al. 2021

Turk J Pediatr

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Background. Mucolipidosis type 3 gamma (ML-IIIγ) is an autosomal recessive, rare and slowly progressive lysosomal storage disease. Short stature, restricted joint mobility, thick skin, and flat face with mildly coarse features are major clinical findings. It usually manifests in the third year. With advancing age, claw hand deformities, carpal tunnel syndrome, and scoliosis may develop. Morbidity is determined mainly by skeletal involvement. N-acetyl glucosamine-1 phospotransferase enzyme is composed of 2α, 2β and 2γ subunits. The active enzyme is essential in the transport of hydrolases to the lysosomes, via addition of mannose-6-phosphate in the Golgi apparatus. GNPTG gene encodes the γ2 subunits, and biallelic mutations cause ML-IIIγ. Case.A previously healthy 14-year-old male patient had leg pain after the age of nine, and was admitted with short stature, mild coarse face, pectus deformity, digital stiffness, scoliosis, genu valgum and mitral valve prolapse. He did not have intellectual disability or corneal clouding. Radiographs showed irregularities in the acetabular roof and proximal epiphyses of the femur and irregularities in the end plates of vertebral bodies. A novel homozygous missense variant in the exon 5 of GNPTG, c.316G>T, confirmed the diagnosis of ML-IIIγ. Juvenile idiopathic arthritis (JIA), progressive pseudorheumatoid dysplasia (PPRD), ML-II, ML-IIIαβ, galactosialidosis and mucopolysaccharidosis should be considered in the differential diagnosis.Conclusions. ML-IIIγ should be kept in mind in populations with high consanguineous marriage rates or with possible founder effect, in patients with short stature and skeletal destruction. Genetic tests should be planned for a definitive diagnosis.

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Genetic Testing of a Large Consanguineous Pakistani Family Affected with Mucolipidosis III Gamma Through Next-Generation Sequencing

Cited by 2 publications

References 9 publications

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

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

The rare reason of pain in hip girdle: Mucolipidosis type 3 gamma

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