Segawa syndrome caused by TH gene mutation and its mechanism

Abstract

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare neurotransmitter disease. The decrease in dopamine caused by tyrosine hydroxylase (TH) gene mutation may lead to dystonia, tremor and severe encephalopathy in children. Although the disease caused by recessive genetic mutation of the tyrosine hydroxylase (TH) gene is rare, we found that the clinical manifestations of seven children with tyrosine hydroxylase gene mutations are similar to dopa-responsive dystonia. To explore the clinical manifestations and possible pathogenesis of the disease, we analyzed the clinical data of seven patients. Next-generation sequencing showed that the TH gene mutation in three children was a reported homozygous mutation (c.698G>A). At the same time, two new mutations of the TH gene were found in other children: c.316_317insCGT, and c.832G>A (p.Ala278Thr). We collected venous blood from four patients with Segawa syndrome and their parents for real-time quantitative polymerase chain reaction analysis of TH gene expression. We predicted the structure and function of proteins on the missense mutation iterative thread assembly refinement (I-TASSER) server and studied the conservation of protein mutation sites. Combined with molecular biology experiments and related literature analysis, the qPCR results of two patients showed that the expression of the TH gene was lower than that in 10 normal controls, and the expression of the TH gene of one mother was lower than the average expression level. We speculated that mutation in the TH gene may clinically manifest by affecting the production of dopamine and catecholamine downstream, which enriches the gene pool of Segawa syndrome. At the same time, the application of levodopa is helpful to the study, diagnosis and treatment of Segawa syndrome.

Tyrosine hydroxylase variants influence protein expression, cellular localization, stability, enzymatic activity and the physical interaction between tyrosine hydroxylase and GTP cyclohydrolase 1

“…BioPKU currently lists 761 variants of TH, some of them classified as probably benign, some of them as pathogenic and some of them as VUS. Four variants affecting the promoter region of the protein have been described 26,27 and around 30 nonsense variants. 27,28 Variants in the splice sites of introns of the TH gene have also been reported, 29,30 but most of the variants found in patients are missense variants.…”

“…Four variants affecting the promoter region of the protein have been described 26,27 and around 30 nonsense variants. 27,28 Variants in the splice sites of introns of the TH gene have also been reported, 29,30 but most of the variants found in patients are missense variants. p.R233H (Dutch variant), 31,32 Note: Half-life of each protein variant as calculated by GraphPad Prism using the raw data of proteinase K digestion based on nonlinear fitting with one phase decay.…”

Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock‐in mouse model

“…Tyrosine hydroxylase deficiency (THD) is a rare autosomal recessive inherited metabolic disorder caused by variants in tyrosine hydroxylase (TH, OMIM 191290). [1][2][3] TH is a nonheme iron-dependent enzyme that catalyzes the hydroxylation of L-Tyr to L-Dopa, using molecular oxygen as an additional substrate and tetrahydrobiopterin (BH 4 ) as a cofactor. 4 This is the rate-limiting step in the biosynthesis of catecholamines, such as dopamine, norepinephrine and epinephrine, 5 where the essential role of the cofactor explains the association of variants in genes involved in the synthesis of BH 4 with deficient catecholamine synthesis.…”

“…Tyrosine hydroxylase deficiency (THD) is a rare autosomal recessive inherited metabolic disorder caused by variants in tyrosine hydroxylase ( TH , OMIM 191290) 1–3 . TH is a non‐heme iron‐dependent enzyme that catalyzes the hydroxylation of L‐Tyr to L‐Dopa, using molecular oxygen as an additional substrate and tetrahydrobiopterin (BH 4 ) as a cofactor 4 .…”

Case report: Clinical, imaging, and genetic characteristics of type B niemann pick disease combined with segawa syndrome diagnosed via dual gene sequencing

“…The onset of neurological symptoms in these patients is later than that in NPA and is more indolent. Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare neurotransmitter disease with a prevalence rate of 0.5 per one million people (Dobricic et al, 2017) The associated decrease in dopamine caused by a mutation in the gene encoding tyrosine hydroxylase (TH) may lead to dystonia, tremor, and severe encephalopathy (Wang et al, 2022)This report presents the case of a patient with concurrent NPB and Segawa syndrome. The 21-year-old female presented with a 10-year history of facial skin tightness, gradual hardening of her skin, disappearance of her forehead lines, deformation of her finger joints in both hands, and shortness of breath, with no apparent cause.…”