“…The frequency and worldwide distribution of the HGSNAT mutations in 25 new MPSIIIC index patients together with those previously reported (Ali Pervaiz et al, ; Canals et al, ; Coutinho et al, ; Fan et al, , ; Fedele & Hopwood, ; Feldhammer, Durand, Mrazova, et al, ; Hrebicek et al, ; Hu et al, ; Huh et al, ; Matos et al, ; Ouesleti et al, , ; Ruijter et al, ; Velasco et al, ) are summarized in Figure . The data show that Europe, South America, and Western Asia are so far the regions with the highest number of families reported with molecular diagnosis of MPSIIIC.…”
Section: Resultssupporting
confidence: 62%
“…Mutations in the HGSNAT gene have been identified in MPSIIIC patients from several countries in Europe (Belarus, Belgium, Czech Republic, Finland, Germany, Greece, Ireland, Italy, Poland, Portugal, Spain, the Netherlands, and the UK), North Africa (Morocco and Tunisia), Asia (Turkey, Pakistan, Singapore, and South Korea), North (Canada and USA; Ali Pervaiz et al, ; Canals et al, ; Coutinho et al, ; Fan et al, ; Fan, Tkachyova, Sinha, Rigat, & Mahuran, ; Fedele & Hopwood, ; Fedele et al, ; Feldhammer, Durand, Mrazova, et al, ; Hrebicek et al, ; Hu et al, ; Huh et al, ; Matos et al, ; Ouesleti et al, , ; Ruijter et al, ) and South America (Argentina and Colombia; Canals et al, ; Velasco et al, ). Approximately 30% of all MPSIIIC variants are shared between different populations suggesting the existence of a common ancestor.…”
Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan‐α‐glucosaminide N‐acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease‐causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice‐site mutation c.494−1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372−2G>A, and c.234+1G>A present in cis with c.564‐98T>C and c.710C>A rare single‐nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease‐causing variants, and reveal the evolutionary history of MPSIIIC.
“…The frequency and worldwide distribution of the HGSNAT mutations in 25 new MPSIIIC index patients together with those previously reported (Ali Pervaiz et al, ; Canals et al, ; Coutinho et al, ; Fan et al, , ; Fedele & Hopwood, ; Feldhammer, Durand, Mrazova, et al, ; Hrebicek et al, ; Hu et al, ; Huh et al, ; Matos et al, ; Ouesleti et al, , ; Ruijter et al, ; Velasco et al, ) are summarized in Figure . The data show that Europe, South America, and Western Asia are so far the regions with the highest number of families reported with molecular diagnosis of MPSIIIC.…”
Section: Resultssupporting
confidence: 62%
“…Mutations in the HGSNAT gene have been identified in MPSIIIC patients from several countries in Europe (Belarus, Belgium, Czech Republic, Finland, Germany, Greece, Ireland, Italy, Poland, Portugal, Spain, the Netherlands, and the UK), North Africa (Morocco and Tunisia), Asia (Turkey, Pakistan, Singapore, and South Korea), North (Canada and USA; Ali Pervaiz et al, ; Canals et al, ; Coutinho et al, ; Fan et al, ; Fan, Tkachyova, Sinha, Rigat, & Mahuran, ; Fedele & Hopwood, ; Fedele et al, ; Feldhammer, Durand, Mrazova, et al, ; Hrebicek et al, ; Hu et al, ; Huh et al, ; Matos et al, ; Ouesleti et al, , ; Ruijter et al, ) and South America (Argentina and Colombia; Canals et al, ; Velasco et al, ). Approximately 30% of all MPSIIIC variants are shared between different populations suggesting the existence of a common ancestor.…”
Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan‐α‐glucosaminide N‐acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease‐causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice‐site mutation c.494−1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372−2G>A, and c.234+1G>A present in cis with c.564‐98T>C and c.710C>A rare single‐nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease‐causing variants, and reveal the evolutionary history of MPSIIIC.
“…Van Schaftingen and coworkers subsequently identified the D2HGDH gene (GeneBank 728294, NM_152783, MIM# 609186), which encodes a d -2-hydroxyglutarate dehydrogenase (D-2-HGDH) with considerable specificity for D-2-HG. Subsequent detection of D2HGDH mutations in patients with D-2-HGA confirmed the identity of this cDNA and documented the genetic lesions (Misra et al 2005; Struys et al 2005a, b; Haliloglu et al 2009; Kranendijk et al 2010a; Pervaiz et al 2011). Twenty six patients have thus far been identified, harboring 31 mutations spread across the D2HGDH coding sequence (Fig.…”
Section: D-2-hydroxyglutaric Aciduria Type I and Ii (Mim# 600721 And mentioning
confidence: 76%
“…Accordingly, patients harboring pathogenic homozygous, or compound heterozygous mutations, in the D2HGDH gene are denoted D-2-HGA type I (∼50% of the D-2-HGA population), and the autosomal-recessive inheritance pattern has been confirmed by genetic characterization of parental DNA samples.Fig. 4Mutations reported in D2HGDH (Misra et al 2005; Struys et al 2005a, b; Haliloglu et al 2009; Kranendijk et al 2010a; Pervaiz et al 2011)…”
Section: D-2-hydroxyglutaric Aciduria Type I and Ii (Mim# 600721 And mentioning
confidence: 99%
“…Mutations reported in D2HGDH (Misra et al 2005; Struys et al 2005a, b; Haliloglu et al 2009; Kranendijk et al 2010a; Pervaiz et al 2011)…”
Section: D-2-hydroxyglutaric Aciduria Type I and Ii (Mim# 600721 And mentioning
The organic acidurias d-2-hydroxyglutaric aciduria (D-2-HGA), l-2-hydroxyglutaric aciduria (L-2-HGA), and combined d,l-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. Accumulation of d-2-hydroxyglutarate (D-2-HG) and/or l-2-hydroxyglutarate (L-2-HG) in body fluids are the biochemical hallmarks of these disorders. The current review describes the knowledge gathered on 2-hydroxyglutaric acidurias (2-HGA), since the description of the first patients in 1980. We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires.
D‐2‐hydroxyglutaric aciduria Type I (D‐2‐HGA Type I), a neurometabolic disorder with a broad clinical spectrum, is caused by recessive variants in the D2HGDH gene encoding D‐2‐hydroxyglutarate dehydrogenase (D‐2‐HGDH). We and others detected 42 potentially pathogenic variants in D2HGDH of which 31 were missense. We developed functional studies to investigate the effect of missense variants on D‐2‐HGDH catalytic activity. Site‐directed mutagenesis was used to introduce 31 missense variants in the pCMV5‐D2HGDH expression vector. The wild type and missense variants were overexpressed in HEK293 cells. D‐2‐HGDH enzyme activity was evaluated based on the conversion of [2H4]D‐2‐HG to [2H4]2‐ketoglutarate, which was subsequently converted into [2H4]L‐glutamate and the latter quantified by LC‐MS/MS. Eighteen variants resulted in almost complete ablation of D‐2‐HGDH activity and thus, should be considered pathogenic. The remaining 13 variants manifested residual activities ranging between 17% and 94% of control enzymatic activity. Our functional assay evaluating the effect of novel D2HGDH variants will be beneficial for the classification of missense variants and determination of pathogenicity.
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