Mutational spectrum of PTS gene and in silico pathological assessment of a novel variant in Mexico

Fernández-Lainez, Cynthia; Ibarra-González, Isabel; Alcántara-Ortigoza, Miguel Ángel; Fernández-Hernández, Liliana; Enríquez-Flores, Sergio; Ángel, Ariadna González-del; Blau, Nenad; Thöny, Beat; Guillén-López, Sara; Belmont-Martínez, Leticia; Ruiz–García, Matilde; Vela-Amieva, Marcela

doi:10.1016/j.braindev.2018.03.014

Cited by 5 publications

(7 citation statements)

References 20 publications

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“… HP, phenomizer code; HPA, hyperphenylalaninemia; HRMS, high-risk metabolicscreening; NA, not available; NBS, newborn screening; RV: Reference value. ✦ previously reported Fernandez-Laninez et al, 2018 . New variants are highlighted in bold.…”

Section: Resultsmentioning

confidence: 92%

“…Three missense variants, p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys), were modeled ( Figures 1 – 3 ). The most common likely pathogenic variant, p.(Ala111Ser), was previously modeled by our group ( Fernández-Lainez et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

“…These 14 patients were included in the present study, and their medical follow-up was available for periods ranging from 2 to 31 years. DHPR activity and blood and urine pterin profiles were available only in the four PTPS-deficient patients previously published ( Fernández-Lainez et al, 2018 ). Herein, we provide updated medical follow-up.…”

Section: Methodsmentioning

confidence: 99%

“…Treatment includes the prescription of drugs such as L-DOPA, 5-hydroxytryptophan, and BH4 (sapropterin), among others ( Opladen et al, 2020 ). In low- or middle-income countries, where HPA NBS programs are still under development, routine biochemical and/or molecular differential diagnosis between PAH and BH4D is not always available ( Fernández-Lainez et al, 2018 ). BH4D can lead to uncommon, highly heterogeneous, and progressive neurological phenotypes attributable to neurotransmitter dysfunction, which are characteristically unresponsive to low-Phe nutritional treatment ( Blau, 2001 ; Himmelreich et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

et al. 2022

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Background: Pterin profiles or molecular analyses of hyperphenylalaninemia (HPA) caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin deficiency (BH4D) are not always available in low- or middle-income countries, including Mexico, limiting information regarding the phenotypic and genotypic characteristics of patients exhibiting BH4D.Objective: To report the genotypes underlying BH4D and the clinical presentation in unrelated Mexican HPA pediatric patients with normal PAH genotypes who attended a single metabolic reference center in Mexico.Methods: Automated Sanger sequencing of the PTS, QDPR, and PCBD1 genes of 14 HPA patients was performed. Predicted effects on protein structure caused by missense variants were assessed by in silico protein modeling.Results and discussion: A high prevalence of BH4D was noted in our HPA cohort (9.8%, N = 14/142). Clinically relevant biallelic genotypes were identified in the PTS (N = 7/14 patients), QDPR (N = 6/14 patients), and PCBD1 (N = 1/14 patients) genes. Four novel QDPR variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G>T or p.(?), c.214G>T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. In silico protein modeling of six missense variants of PTS [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], QDPR [p.(Cys161Phe) and p.(Pro172Leu)], and PCBD1 [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in three patients) were noted in all patients with biallelic QDPR genotypes and in 5/7 patients bearing biallelic PTS genotypes. The single homozygous PCBD1 p.(Glu97Lys) patient remains asymptomatic.Conclusion: A higher proportion of BH4D (9.8 vs. 1%–2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the PTS-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

et al. 2022

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“…BH4 is an essential cofactor for levodopa, serotonin, and tyrosine syntheses. 6‐Pyruvoyl‐tetrahydropterin synthase (PTPS) is involved in BH4 biosynthesis and its deficiency is the most common BH4 disorder, causing an autosomal‐recessive condition clinically characterized by neurodevelopmental delay, truncal hypotonia, extrapyramidal features, and swallowing difficulties . Behavioral problems, such as irritability, obsessive‐compulsive disorder, and aggressiveness, are also common .…”

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confidence: 99%

Combined Dystonia With Self‐Mutilation in 6‐Pyruvoyl‐Tetrahydropterin Synthase (PTPS) Deficiency: A Case Report

Latorre

Salgado

Salari

et al. 2018

Movement Disord Clin Pract

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Genotypic variants of the tetrahydrobiopterin (BH4) biosynthesis genes in patients with hyperphenylalaninemia from different regions of Iran

Nezhad,

Aligoodarzi,

Rostami

et al. 2023

Molec Gen & Gen Med

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BackgroundHyperphenylalaninemia (HPA) is a metabolic disorder classified into phenylalanine‐4‐hydroxylase (PAH) and non‐PAH deficiency. The latter is produced by mutations in genes involved in the tetrahydrobiopterin (BH4) biosynthesis pathway and DNAJC12 pathogenetic variants. The BH4 metabolism, including de novo biosynthesis involved genes (i.e., guanosine 5′‐triphosphate cyclohydrolase I (GTPCH/GCH1), sepiapterin reductase (SR/SPR), 6‐pyruvoyl‐tetrahydropterin synthase (PTPS/PTS)), and two genes that play roles in cofactor regeneration pathway (i.e., dihydropteridine reductase (DHPR/QDPR) and pterin‐4α‐carbinolamine dehydratase (PCD/PCBD1)). The subsequent systemic hyperphenylalaninemia and monoamine neurotransmitter deficiency lead to neurological consequences. The high rate of consanguineous marriages in Iran substantially increases the incidence of BH4 deficiency.MethodsWe utilized the Sanger sequencing technique in this study to investigate 14 Iranian patients with non‐PAH deficiency. All affected subjects in this study had HPA and no mutation was detected in their PAH gene.ResultsWe successfully identified six mutant alleles in BH4‐deficiency‐associated genes, including three novel mutations: one in QDPR, one in PTS, and one in the PCBD1 gene, thus giving a definite diagnosis to these patients.ConclusionIn this light, appropriate patient management may follow. The clinical effect of reported variants is essential for genetic counseling and prenatal diagnosis in the patients' families and significant for the improvement of precision medicine.

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Mutational spectrum of PTS gene and in silico pathological assessment of a novel variant in Mexico

Cited by 5 publications

References 20 publications

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

Combined Dystonia With Self‐Mutilation in 6‐Pyruvoyl‐Tetrahydropterin Synthase (PTPS) Deficiency: A Case Report

Genotypic variants of the tetrahydrobiopterin (BH4) biosynthesis genes in patients with hyperphenylalaninemia from different regions of Iran

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