Two novel mutations in <i>SLC6A8</i> cause creatine transporter defect and distinctive X‐linked mental retardation in two unrelated Dutch families

Mancini, Grazia M.S.; Catsman‐Berrevoets, Coriene E.; Coo, I.F.M. de; Aarsen, Femke K.; Kamphoven, J.H.J.; Huijmans, J. G. M.; Durán, Marinus; Knaap, Marjo S. van der; Jakobs, Cornelis; Salomons, Gajja S.

doi:10.1002/ajmg.a.30473

Cited by 50 publications

(46 citation statements)

References 20 publications

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“…In AGAT deficiency, total Cr levels in cortical gray matter are decreased to 12% of age-matched controls (Battini et al 2002). In GAMT deficiency, CSF Cr levels are strongly decreased (\2 lM) (Schulze et al 1997(Schulze et al , 2003Ensenauer et al 2004), while in cortical gray matter total Cr was measured in the 0.2-1.5mM range (Stöckler et al 1994;Mancini et al 2005).…”

Section: Creatine and Guanidinoacetate Within Normal Versus Creatine-mentioning

confidence: 99%

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT-and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not coexpressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT-to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

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Section: Creatine and Guanidinoacetate Within Normal Versus Creatine-mentioning

confidence: 99%

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

et al. 2011

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“…In patients, creatine deficiency syndromes have several common clinical manifestations, including cognitive dysfunction with mental retardation, poor language skills, and autism spectrum disorders (9)(10)(11)(12)(13)(14)(15). Proton magnetic resonance spectroscopy (MRS) of affected patients shows an absence or dramatic diminution of the creatine peak, with relatively normal levels of n-acetyl aspartate (9,16,17).…”

Section: Introductionmentioning

confidence: 99%

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

Kurosawa¹,

deGrauw²,

Lindquist³

et al. 2012

J. Clin. Invest.

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“…GAMT deficiency is characterized by accumulation of guanidinoacetic acid in brain and body fluids and shows intractable seizures and the movement disorder (Sykut-Cegielska et al, 2004). GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CT1 defect is an X-linked disorder (Mancini et al, 2005. Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiency (Battini et al, 2006, Schulze et al, 2006, whereas it does not work on CT1 deficiency.…”

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Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis

Wang¹,

Zhang²,

Shao³

et al. 2007

Int. J. Dev. Biol.

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Glycine amidinotransferase (AGAT or GATM), guanidinoacetate methyltransferase (GAMT) and creatine transporter (CT1) are three proteins involved in the synthesis and uptake of creatine. The expression patterns of these three genes were examined in zebrafish embryos by whole mount in situ hybridization followed by histological sectioning. Expression of agat first appeared in the yolk syncytial layer (YSL) at the gastrula stage and was progressively up regulated during gastrulation. As development proceeds, agat was expressed in the mature somites during the segmentation stage and in the liver at 48 hpf. gamt showed a similar expression pattern to that of agat during embryogenesis. It was first detected in the center of the yolk from the cleavage to the gastrula stage. At the bud stage, its expression shifted to the YSL. gamt was also transiently expressed in the mature somites from 16 hpf to 24 hpf and became strongly expressed in the liver and in epithelial cells of the gut at 48 hpf. ct1 was initially uniformly expressed from the cleavage to the early segmentation stage; it was then strongly expressed in all the somites till 30 hpf and in the gut of 48 hpf embryos. However, ct1 transcripts also appeared in the central nervous system during the segmentation stage, but not in the YSL, the yolk or the liver. Our data reveal for the first time distinct and unique patterns of expression of the creatine metabolism genes agat, gamt and ct1 during zebrafish embryogenesis. KEY WORDS: agat, gamt, ct1, zebrafish, developmental expressionThe creatine metabolism plays a crucial role for keeping the normal life of vertebrates. Endogenous creatine is synthesized by a two-step mechanism involving two enzymes: glycine amidinotransferase (AGAT or GATM) and guanidinoacetate methyltransferase (GAMT). Creatine is taken up by cells through CT1, a specific creatine transporter (Wyss and KaddurahDaouk, 2000). Defects of AGAT, GAMT and CT1 result in three kinds of creatine deficiency syndromes (CDS) occurring mostly in children (Schulze, 2003). The common clinical feature of three CDS is developmental delay/regression, mental retardation and severe disturbance of their expressive and cognitive speech (van der . The biochemical characteristics of CDS include severe depletion of creatine/phosphocreatine in the brain, as well as changes in creatine and creatinine concentrations in body fluids , Cecil et al., 2001, Schulze, 2003, Stromberger et al., 2003, Almeida et al., 2004, Sykut-Cegielska et al., 2004. GAMT deficiency is characterized by accumulation of guanidinoacetic acid in brain and body fluids and shows intrac- Abbreviations used in this paper: AGAT (or GATM), glycine amidinotransferase; GAMT, guanidinoacetate methyltransferase; CDS, creatine deficiency syndromes; CT1, creatine transporter 1; YSL, yolk syncytial layer. al., 2004). GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CT1 defect is an X-linked disorder (Mancini et al., 2005. Treatment with oral creatine supplementation is in part successful ...

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Two novel mutations in SLC6A8 cause creatine transporter defect and distinctive X‐linked mental retardation in two unrelated Dutch families

Cited by 50 publications

References 20 publications

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis

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