Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia-cystinuria syndrome

Chabrol, B.; Martens, Kevin; Meulemans, Sandra; Cano, Amparo; Jaeken, Jaak; Matthijs, Gert; Creemers, John W.M.

doi:10.1136/bcr.08.2008.0719

Cited by 14 publications

(12 citation statements)

References 19 publications

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“…f: Growth curve of patient 2, with standard deviation score curves as indicated. g: Junction fragment PCR of patient 2 (1), her mother (2), father (3) and a control (4). The fragment is absent in the control.…”

Section: Patientmentioning

confidence: 98%

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Two novel deletions in hypotonia–cystinuria syndrome

Régal

Aydin

Dieltjens

et al. 2012

Molecular Genetics and Metabolism

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Section: Patientmentioning

confidence: 98%

“…Two other deletions involve C2orf34 (OMIM ID: 609559) in addition. Homozygous deletion of these 3 genes causes the more severe "atypical HCS" [4]. The 2p21 deletion syndrome in addition involves a fourth gene, PPM1B (OMIM ID: 603770), and is clinically the most severe [5,6].…”

Section: Introductionmentioning

confidence: 99%

Two novel deletions in hypotonia–cystinuria syndrome

Régal

Aydin

Dieltjens

et al. 2012

Molecular Genetics and Metabolism

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“…Other mammalian members of the prolyl peptidase family include the dipeptidyl peptidases, such as the anti-diabetic target dipeptidyl peptidase 4 (DPP4) (4), and the recently characterized prolyl endopeptidase-like (PrepL) (5), which has been genetically linked to hypotoniacystinuria syndrome (HCS) (6–8). Prep has been of general interest because of its unique biochemical activity as a proline endopeptidase.…”

mentioning

confidence: 99%

Peptidomics of Prolyl Endopeptidase in the Central Nervous System

et al. 2009

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Prolyl endopeptidase (Prep) is a member of the prolyl peptidase family and is of interest due to its unique biochemistry and connections to cognitive function. Using an unbiased mass spectrometry (MS)-based peptidomics platform, we identified Prep regulated peptides in the central nervous system (CNS) of mice by measuring changes in the peptidome as a function of Prep activity. This approach was validated by the identification of known Prep substrates, such as the neuropeptide substance P and thymosin-β4, the precursor to the bioactive peptide Ac-SDKP. In addition to these known substrates, we also discovered that Prep regulates many additional peptides, including additional bioactive peptides and proline rich peptides (PRPs). Biochemical experiments confirmed that some of these Prep regulated peptides are indeed substrates of the enzyme. Moreover, these experiments also supported the known preference of Prep for shorter peptides, while revealing a previously unknown cleavage site specificity of Prep when processing certain multi-proline containing peptides, including PRPs. The discovery of Prep regulated peptides implicates Prep in new biological pathways and provides insights into the biochemistry of this enzyme.Prolyl endopeptidase (Prep), also commonly referred to as prolyl oligopeptidase (POP) (EC 3.4.21.26), was first identified as an oxytocin cleaving activity in the human uterus (1) and is part of the prolyl peptidase family of enzymes (2,3). Other mammalian members of the prolyl peptidase family include the dipeptidyl peptidases, such as the anti-diabetic target dipeptidyl peptidase 4 (DPP4) (4), and the recently characterized prolyl endopeptidase-like (PrepL) (5), which has been genetically linked to hypotoniacystinuria syndrome (HCS) (6)(7)(8). Prep has been of general interest because of its unique biochemical activity as a proline endopeptidase. Unlike the dipeptidyl peptidases, which are restricted to N-terminal dipeptide cleavage (3,9), Prep proteolysis occurs at internal prolines in a peptide (10)(11)(12). On the basis of the known preference of Prep for cleavage at a proline, many proline-containing bioactive peptides have been tested, and identified, as Prep substrates in vitro (12). These substrates range from the tripeptide, thyrotropin-releasing hormone, to a 31 amino acid peptide, beta endorphin (2,13).Correspondence to: Alan Saghatelian, saghatelian@chemistry.harvard.edu. *To whom correspondence should be addressed. Phone: (617) . saghatelian@chemistry.harvard.edu. Supporting Information. ABPP gels with prolyl peptidases and S17092, Prep activity assay showing heat inactivation, graph with fold changes of peptides at one hour and 4 hours of inhibition, graph of CGRP(1-37) levels after one hour of inhibition, kinetic plots of CGRP analogs with wild type and mutant Prep, table with kinetic parameters of CGRP analogs with wild type and mutant Prep with kcat/Km calculated as second order rate constant, MALDI-MS spectrum of the reaction of unacetylated Hsp12a(2-23) with Prep, circula...

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“…The main phenotypical features are infantile hypotonia, poor sucking and associated feeding problems, growth hormone deficiency leading to growth restriction, mild facial dysmorphic features and cystinuria type AA [12]. Atypical hypotonia-cystinuria syndrome, which features disruption to three contiguous genes, SLC3A1, PREPL and C2orf34, produces an intermediate phenotype featuring mild to moderate intellectual disability in addition to the features of hypotonia-cystinuria syndrome [13]. The 2p21 deletion syndrome, resulting from homozygous loss of four contiguous genes, SLC3A1, PREPL, C2orf34 and PPM1B, produces a more severe phenotype, as expected, owing to the higher number of genes affected [4].…”

Section: Syndromes Associated With Cystinuriamentioning

confidence: 99%

Cystinuria: A Review of Inheritance Patterns, Diagnosis, Medical Treatment and Prevention of Stones

Sayer¹,

Hill²

2017

Updates and Advances in Nephrolithiasis - Pathophysiology, Genetics, and Treatment Modalities

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Cystinuria is a rare inherited renal stone disease. Mutations in two genes SLC3A1 and SLC7A9 underlie this condition, encoding proteins that facilitate dibasic amino acid exchange which are expressed in the gut and the proximal tubule of the kidney. Genetic studies now allow precise genotyping of patients who may have both autosomal dominant and autosomal recessive patterns of disease. The disorder is characterised by the urinary loss of cystine, lysine, ornithine, and arginine, and the insolubility of cystine gives rise to crystalluria and cysteine-containing renal stones. Although an inherited condition, it may present at any age. Clinical management combines lifestyle advice and preventative medical therapy. However, many patients require surgical interventions to remove problematic stones from the urinary tract. Preventative therapies include increased fluid intake, alkalinization of the urine, and the use of cystine-binding drugs, including penicillamine and tiopronin, which form soluble heterodimers with cystine.

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Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia-cystinuria syndrome

Cited by 14 publications

References 19 publications

Two novel deletions in hypotonia–cystinuria syndrome

Two novel deletions in hypotonia–cystinuria syndrome

Peptidomics of Prolyl Endopeptidase in the Central Nervous System

Cystinuria: A Review of Inheritance Patterns, Diagnosis, Medical Treatment and Prevention of Stones

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