Mutations responsible for 3-phosphoserine phosphatase deficiency

Veiga‐da‐Cunha, Maria; Collet, Jean-François; Prieur, Benoît E.; Jaeken, Jaak; Peeraer, Yves; Rabbijns, Anja; Schaftingen, Emile Van

doi:10.1038/sj.ejhg.5201083

Cited by 38 publications

(29 citation statements)

References 19 publications

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“…The biochemical hallmark of this disorder is a significantly reduced concentration of L-serine and, to a variable degree, glycine, in cerebrospinal fluid (CSF) and plasma (de Koning et al 2000). Deficiencies of the other two enzymes involved in the L-serine biosynthesis show clinical phenotypes (severe neurological symptoms, severe psychomotor retardation, and seizures) similar to that found in 3-PGDH deficiency (Hart et al 2007; Jaeken et al 1997; Veiga-da-Cunha et al 2004). Decreased serine in CSF has also been described in cases in which the biochemical defect remained unsolved.…”

Section: Introductionmentioning

confidence: 65%

Fatal cerebral edema associated with serine deficiency in CSF

Keularts

Leroy

Rubio‐Gozalbo

et al. 2010

J of Inher Metab Disea

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Two young girls without a notable medical history except for asthma presented with an acute toxic encephalopathy with very low serine concentrations both in plasma and cerebrospinal fluid (CSF) comparable to patients with 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. Clinical symptoms and enzyme measurement (in one patient) excluded 3-PGDH deficiency. Deficiencies in other serine biosynthesis enzymes were highly unlikely on clinical grounds. On basis of the fasting state, ketone bodies and lactate in plasma, urine and CSF, we speculate that reduced serine levels were due to its use as gluconeogenic substrate, conversion to pyruvate by brain serine racemase or decreased L-serine production because of a lack of glucose. These are the first strikingly similar cases of patients with a clear secondary serine deficiency associated with a toxic encephalopathy.

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Section: Introductionmentioning

confidence: 65%

Fatal cerebral edema associated with serine deficiency in CSF

Keularts

Leroy

Rubio‐Gozalbo

et al. 2010

J of Inher Metab Disea

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“…Both rs4947534 and rs4948102 are within the gene phosphoserine phosphatase (PSPH), the protein product of which catalyzes the final step in the synthesis of serine by converting phosphoserine into serine (Figure 3). PSPH mutations may cause phosphoserine phosphatase deficiency, a syndrome with multiple clinical features including reduced plasma levels of serine 68 .…”

Section: Suggestive Locimentioning

confidence: 99%

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

et al. 2017

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Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genomewide association study (GWAS) with 476 cases and 1733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10 -8 ) were identified at 3 independent loci (rs73171800 at 5q14.3, P = 7.74 × 10 -17 ; rs715 at 2q34, P = 9.97 × 10 -14 ; rs477992 at 1p12, P = 2.60 × 10 -12 ) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences of blood serum levels of glycine (P = 4.04 × 10 -6 ) and serine (P = 2.48 × 10 -4 ) between MacTel cases and controls.MacTel cases typically present at 40-60 years with abnormal right-angled juxtafoveolar capillaries and parafoveal telangiectasias. It is an uncommon disease with a 0.0045-0.1% population prevalence and no obvious sex bias [1][2][3] . Retinal lesions typically co-present with MacTel, including retinal transparency, outer retinal and choroidal neovascularization, lamellar holes or foveal cysts, photoreceptor dysfunction, minimal exudation, yellow-white parafoveal crystals, and retinal pigment epithelial (RPE) pigmentation abnormalities and atrophy. Central vision impairment and decreased visual acuity are the usual clinical outcomes. MacTel is a bilateral disease, but asymmetry of the eyes for disease severity and presence of lesions is possible. The lesions also occur in 0.06-1.18% of the general population 2 .Risk factors for MacTel are largely unknown, however associations have been observed with smoking 2,4 , diabetes 5,6 , high BMI 6 , hypertension 6 and obesity 6 .Observations of MacTel affected monozygotic twins 4,[7][8][9] , and multiplex families with vertical transmissions of MacTel 1,5,[9][10][11][12] , suggest a genetic etiology for the disease. The late-age of onset, low penetrance and variable phenotype as exemplified by asymptomatic affected relatives 9 , and positive and negative misdiagnoses, complicate the discovery of genetic variants predisposing to MacTel. We previously screened 27 candidate genes in 8 unrelated MacTel cases but found no causative mutations 13 . Linkage analysis of 17 families with MacTel individuals identified a 15.3Mb locus on chromosome 1q41-42.2 (LOD=3.45), however sequencing of the underlying genes revealed no causative mutations 14 . Results Discovery GWAS stageThe GWAS discovery stage included genotype data for 6,312,048 single nucleotide polymorphisms (SNPs) after quality control and imputation (including 1,093,805 SNPs genotyped on the Illumina Omni SNP chips) in 476 MacTel cases and 1,733 controls (see Table 1 and Online Methods). This sample size was large enough to achieve power of at least 0.90 for risk variants with allele frequencies of 0.10-...

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“…Recently, two patients have been reported with a deficiency of PSAT (MIM# 610992) [Hart et al, 2007]. PSPH deficiency (MIM# 172480) has been identified until now in only one patient who presented with Williams syndrome [Jaeken et al, 1997;Veiga-da-Cunha et al, 2004]. 3-PGDH deficiency was the first serine-biosynthesis disorder to be reported [Jaeken et al, 1996;Klomp et al, 2000;Pind et al, 2002].…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics

et al. 2009

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Three-phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare recessive inborn error in the biosynthesis of the amino acid L-serine characterized clinically by congenital microcephaly, psychomotor retardation, and intractable seizures. The biochemical abnormalities associated with this disorder are low concentrations of L-serine, D-serine, and glycine in cerebrospinal fluid (CSF). Only two missense mutations (p.V425M and p.V490M) have been identified in PHGDH, the gene encoding 3-PGDH, but it is currently unclear how these mutations in the carboxy-terminal regulatory domain of the protein affect enzyme function. We now describe five novel mutations in five patients with 3-PGDH deficiency; one frameshift mutation (p.G238fsX), and four missense mutations (p.R135W, p.V261M, p.A373T, and p.G377S). The missense mutations were located in the nucleotide binding and regulatory domains of 3-PGDH and did not affect steady-state expression, protein stability, and protein degradation rates. Patients' fibroblasts displayed a significant, but incomplete, reduction in maximal enzyme activities associated with all missense mutations. In transient overexpression studies in HEK293T cells, the p.A373T, p.V425M, and p.V490M mutations resulted in almost undetectable enzyme activities. Molecular modeling of the p.R135W and p.V261M mutations onto the partial crystal structure of 3-PGDH predicted that these mutations affect substrate and cofactor binding. This prediction was confirmed by the results of kinetic measurements in fibroblasts and transiently transfected HEK293T cells, which revealed a markedly decreased V(max) and an increase in K(m) values, respectively. Taken together, these data suggest that missense mutations associated with 3-PGDH deficiency either primarily affect substrate binding or result in very low residual enzymatic activity.

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Mutations responsible for 3-phosphoserine phosphatase deficiency

Cited by 38 publications

References 19 publications

Fatal cerebral edema associated with serine deficiency in CSF

Fatal cerebral edema associated with serine deficiency in CSF

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics

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