GlyT1 encephalopathy: Characterization of presumably disease causing GlyT1 mutations

Hauf, Katharina; Barsch, L.; Bauer, Daniel; Buchert, Rebecca; Armbruster, Anja; Frauenfeld, Leonie; Grasshoff, Ute; Eulenburg, Volker

doi:10.1016/j.neuint.2020.104813

Cited by 7 publications

(8 citation statements)

References 46 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In all cases, parents were consanguineous, and an autosomal recessive inheritance was observed. Two families presented truncating variants [p.(Lys310Phefs*31) and p.(Gln573*)], which resulted in a complete loss of the transporter function (Hauf et al, 2020; Kurolap, Armbruster, et al, 2016). The other two families had missense variants [p.(Ser407Gly) and p.(Val118Met)], which led to a severely diminished activity of the transporter, most likely resulting in a functional knock out under physiological conditions (Alfadhel et al, 2016; Hauf et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…To date, only eight affected individuals from four unrelated families have been reported in the literature. All of them harbored biallelic genetic variants in the gene SLC6A9 , which codifies the protein sodium‐ and chloride‐dependent glycine transporter 1 (GLYT1) (Alfadhel et al, 2016; Kurolap et al, 2016; Hauf et al, 2020). The main function of GLYT1 is to modulate the synaptic concentration of glycine (Betz, Gomeza, Armsen, Scholze, & Eulenburg, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms

Mademont-Soler

Casellas-Vidal

Trujillo

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

GLYT1 encephalopathy is a form of glycine encephalopathy caused by disturbance of glycine transport. The phenotypic spectrum of the disease has not yet been completely described, as only four unrelated families with the disorder have been reported to date. Common features of affected patients include neonatal hypotonia, respiratory failure, encephalopathy, myoclonic jerks, dysmorphic features, and musculoeskeletal anomalies. All reported affected patients harbor biallelic genetic variants in SLC6A9. SNP array together with Sanger sequencing were performed in a newborn with arthrogryposis and severe neurological impairment. The novel genetic variant c.997delC in SLC6A9 was detected in homozygous state in the patient. At protein level, the predicted change is p.(Arg333Alafs*3), which most probably results in a loss of protein function. The variant cosegregated with the disease in the family.A subsequent pregnancy with ultrasound anomalies was also affected. The proband presented the core phenotypic features of GLYT1 encephalopathy, but also a burst suppression pattern on the electroencephalogram, a clinical feature not previously associated with the disorder. Our results suggest that the appearance of this pattern correlates with higher cerebrospinal fluid glycine levels and cerebrospinal fluid/ plasma glycine ratios. A detailed discussion on the possible pathophysiological mechanisms of the disorder is also provided.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms

Mademont-Soler

Casellas-Vidal

Trujillo

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…Human genetical data demonstrated that defects of GlyT but also of Asc-1 functionality lead to severe clinical symptoms. Homozygous mutations in the GlyT1 ( SLC6A9 ) gene have been shown to cause a disease phenotype very similar but not identical to glycine encephalopathy or nonketotic hyperglycinemia [ 88 , 89 , 90 ], a disease previously associated with defects in the glycine cleavage system. Similar to patients suffering from glycine encephalopathy, affected individuals have severe neurological problems reminiscent of the phenotype seen in GlyT1-deficient mice, characterized by hypotonia and severe respiratory depression directly after birth.…”

Section: Pathological Correlates In Humansmentioning

confidence: 99%

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

Eulenburg

Hülsmann

2022

IJMS

View full text Add to dashboard Cite

In addition to being involved in protein biosynthesis and metabolism, the amino acid glycine is the most important inhibitory neurotransmitter in caudal regions of the brain. These functions require a tight regulation of glycine concentration not only in the synaptic cleft, but also in various intracellular and extracellular compartments. This is achieved not only by confining the synthesis and degradation of glycine predominantly to the mitochondria, but also by the action of high-affinity large-capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminals or glial cells surrounding the synapses. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their synergistic functional interaction is only poorly understood. In this review, we summarize our current knowledge of the two high-affinity transporters for glycine, the sodium-dependent glycine transporters 1 (GlyT1; SLC6A9) and 2 (GlyT2; SLC6A5) and the alanine–serine–cysteine-1 transporter (Asc-1; SLC7A10).

show abstract

“…GlyT1-deficit leads to an hyperglycinergic phenotype with hypotonia and motor disorders in GlyT1 −/− -knockout mice and Shocked Zebrasfish-mutant ( Gomeza et al, 2003 ; Tsai et al, 2004 ; Cui et al, 2005 ; Mongeon et al, 2008 ; Hirata et al, 2010 ; Eulenburg et al, 2010 ). Mutations of human SLC6A5 caused glycine encephalopathy with normal serum glycine (OMIM:#617301), a severe metabolic disease that produces hypotonia and respiratory failures in neonatal ( Kurolap et al, 2016 ; Hauf et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A three-sodium-to-glycine stoichiometry shapes the structural relationships of ATB^0,+ with GlyT2 and GlyT1 in the SLC6 family

Rousseau

Bied

et al. 2021

Preprint

View full text Add to dashboard Cite

GlyT2 (SLC6A5), two glycine-specific transporters coupled to 2:1 and 3:1 Na+:Cl-, respectively. However, ATB0,+ stoichiometry that specifies its driving force and electrogenicity remains unsettled. Using the reversal potential slope method, here we demonstrate that ATB0,+-mediated glycine transport is coupled to 3 Na+ and 1 Cl- and has a charge coupling of 2.1 e/glycine. ATB0,+ behaves as a unidirectional transporter with limited e and exchange capabilities. Analysis and computational modeling of the pre-steady-state charge movement reveal higher sodium affinity of the apo-ATB0,+, and a locking trap preventing Na+ loss at depolarized potentials. A 3 Na+/ 1 Cl- stoichiometry substantiates ATB0;+ concentrative-uptake and trophic role in cancers and rationalizes its structural proximity with GlyT2 despite their divergent substrate specificity. Analysis and computational modeling of the pre-steady-state charge movement reveal higher sodium affinity of the apo-ATB0,+, and a locking trap preventing Na+ loss at depolarized potentials. A 3 Na+/ 1 Cl- stoichiometry substantiates ATB0,+ concentrative-uptake and trophic role in cancers and rationalizes its structural proximity with GlyT2 despite their divergent substrate specificity.

show abstract

GlyT1 encephalopathy: Characterization of presumably disease causing GlyT1 mutations

Cited by 7 publications

References 46 publications

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

A three-sodium-to-glycine stoichiometry shapes the structural relationships of ATB^0,+ with GlyT2 and GlyT1 in the SLC6 family

Contact Info

Product

Resources

About

GlyT1 encephalopathy: Characterization of presumably disease causing GlyT1 mutations

Cited by 7 publications

References 46 publications

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms

Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1

A three-sodium-to-glycine stoichiometry shapes the structural relationships of ATB0,+ with GlyT2 and GlyT1 in the SLC6 family

Contact Info

Product

Resources

About

A three-sodium-to-glycine stoichiometry shapes the structural relationships of ATB^0,+ with GlyT2 and GlyT1 in the SLC6 family