Clinical, radiological and computational studies on two novel GNPTG variants causing mucolipidosis III gamma phenotypes with varying severity.

Mucolipidosis III gamma (ML III γ) is a slowly progressive disorder that affects multiple parts of the body such as the skeleton, joints, and connective tissue structures. It is caused by pathogenic variants in the GNPTG gene that provides instructions for producing the γ subunit of GlcNAc-1-phosphotransferase. In this study we aim to characterize clinical findings and biological insights on two novel GNPTG variants causing ML III γ phenotypes with varying severity. We report on two siblings with ML III γ bearing the previously undescribed c.477C > G (p.Y159*) nonsense variant in a homozygous state as well as a patient with ML III γ bearing the novel c.110 + 19_111-17del variant in a homozygous state. These variants were revealed by whole-exome sequencing and Sanger sequencing, respectively. Their parents, who are heterozygotes for the same mutation, are healthy. The clinical and radiographic presentation of ML III γ in our patients who had c.477C > G (p.Y159*) variant is consistent with a relatively severe form of the disease, which is further supported by a working three-dimensional model of the GlcNAc-1-phosphotransferase γ subunit. On the other hand, it is seen that our patient who carries the c.110 + 19_111-17del variant has a milder phenotype. Our findings help broaden the spectrum of GNPTG variants causing ML III γ and offer structural and mechanistic insights into loss of GlcNAc-1-phosphotransferase γ subunit function.

Clinical Characterization of Mucolipidoses II and III: A Multicenter Study.

Mucolipidoses (MLs) II and III are rare lysosomal diseases caused by deficiency of GlcNAc-1-phosphotransferase, and clinical manifestations are multisystemic. Clinical and demographic data from 1983 to 2013 were obtained retrospectively. Twenty-seven patients were included (ML II = 15, ML III α/beta = 9, ML III gamma = 3). The median age at diagnosis was 2.7 years. The predominant clinical presentations were skeletal symptoms. The ML II patients showed physical and cognitive impairment, while the ML III α/beta patients have more somatic abnormalities and usually were delayed in early development as compared with ML III gamma patients. This is the most comprehensive study exploring characteristics of Brazilian patients with MLs II and III.

Mucolipidosis type III gamma: Three novel mutation and genotype-phenotype study in eleven patients.

Mucolipidosis type III gamma (MLIII gamma) is a lysosomal storage disease characterized by joint stiffness, mild coarse face and corneal clouding, which becomes recognizable usually in childhood. Biallelic mutations in the GNPTG gene, which encode the γ subunit of the N-acetylglucosamine-1-phosphotransferase enzyme, are the underlying cause of MLIII gamma. The aim of this study is to evaluate the longitudinal findings and genotype of eleven patients from eight families with MLIII gamma and to establish a genotype-phenotype correlation. The most frequently observed initial finding was stiffness of finger joints, which detected in patients between 18month-olds and five year-olds. However, in four patients presented here, initial finding was knee pain or waddling gait, which started between six-16years of age. All patients also had variable degrees of stiffness on large joints. The longest follow up period was 16years while the shortest was three years and six months. We observed that the patients who had an early onset disease and severe joint stiffness had also rapidly progressive joint involvement mostly localized in hands, shoulders, and hip. However; the patients with late onset and/or mild joint stiffness experienced slowly progressive symptoms. Most patients dropped in their growth curve in time and the ones who were severely affected reached the final height below the third centile. Seven disease-causing mutations, three of them novel, were detected in GNPTG gene. According to our clinical observations c.493_494insC and c.283_284insC mutations lead to a severe phenotype and c.196C>T, c.347_349del, c.652_655delTACT and c.445delG/c.367A>G mutations seemed to generate a milder phenotype.

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

BACKGROUND: Scleroderma is a multisystem disease, characterized by fibrosis of skin and internal organs, immune dysregulation, and vasculopathy. The etiology of the disease remains unknown, but it is likely multifactorial. However, the genetic basis for this condition is defined by multiple genes that have only modest effect on disease susceptibility. METHODS: Three Moroccan siblings, born from non-consanguineous Moroccan healthy parents were referred for genetic evaluation of familial scleroderma. Whole Exome Sequencing was performed in the proband and his parents, in addition to Sanger sequencing that was carried out to confirm the results obtained. RESULTS: Mutation analysis showed two compound heterozygous mutations c.196C>T in exon 4 and c.635_636delTT in exon 9 of GNPTG gene. Sanger sequencing confirmed these mutations in the affected patient and demonstrated that their parents are heterozygous carriers. CONCLUSION: Our findings expand the mutation spectrum of the GNPTG gene and extend the knowledge of the phenotype-genotype correlation of Mucolipidosis Type III gamma. This report also highlights the diagnostic utility of Next Generation Sequencing particularly when the clinical presentation did not point to specific genes.