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

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

doi:10.1136/jmg.2007.055475

Cited by 45 publications

(44 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Homozygous deletion carriers in this family showed HCS and additional features including neonatal seizures and a severe global retardation, indicating that the loss of a third gene in 2p21, PPM1B , also contributes to the clinical spectrum in this family. Meanwhile, additional patients with an intermediate phenotype between HCS and the 2p21 microdeletion syndrome and deletions intermediate in size have been described [47]. …”

Section: The Hypotonia-cystinuria Syndrome and 2p21 Microdeletionsmentioning

confidence: 99%

Cystinuria: an inborn cause of urolithiasis

Eggermann

Venghaus

Zerres

2012

Orphanet Journal of Rare Diseases

102

View full text Add to dashboard Cite

Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b0,+ transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b0,+AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.

show abstract

Section: The Hypotonia-cystinuria Syndrome and 2p21 Microdeletionsmentioning

confidence: 99%

Cystinuria: an inborn cause of urolithiasis

Eggermann

Venghaus

Zerres

2012

Orphanet Journal of Rare Diseases

102

View full text Add to dashboard Cite

show abstract

“…Often a PREPL neighboring gene called solute carrier family 3 (amino acid transporter heavy chain) member 1 ( SLC3A1 ) is also missing. In addition, in some atypical HCS cases, PREPL and SLC3A1 are deleted with another gene, calmodulin-lysine N-methyltransferase ( CAMKMT or C2ORF34 ) [6]. Isolated deletions of SLC3A1 , which is highly expressed in the kidney [7], are known to cause cystinuria [8], suggesting that PREPL is accountable for the other symptoms associated with HCS.…”

Section: Introductionmentioning

confidence: 99%

Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice

et al. 2014

View full text Add to dashboard Cite

Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL) is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS). HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL−/−) mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL−/− mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL+/+) counterparts. A righting assay revealed that PREPL−/− pups took significantly longer than PREPL+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL−/− mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical, cellular and physiological pathways that link PREPL to HCS, and this may eventually lead to new insights in the treatment of this disease.

show abstract

“…Atypical HCS patients present with a phenotype partly similar to 2p21 deletion syndrome such as severe hypotonia at birth, poor feeding, facial dysmorphism, growth retardation and cystinuria but with growth hormone deficiency not observed in the patients of the 2p21 deletion syndrome [3]. In addition, they showed a mild to moderate mental retardation and cytochrome C oxidase deficiency (mitochondrial complex IV) [4].…”

Section: Introductionmentioning

confidence: 99%

Human Calmodulin Methyltransferase: Expression, Activity on Calmodulin, and Hsp90 Dependence

et al. 2012

View full text Add to dashboard Cite

Deletion of the first exon of calmodulin-lysine N-methyltransferase (CaM KMT, previously C2orf34) has been reported in two multigene deletion syndromes, but additional studies on the gene have not been reported. Here we show that in the cells from 2p21 deletion patients the loss of CaM KMT expression results in accumulation of hypomethylated calmodulin compared to normal controls, suggesting that CaM KMT is essential for calmodulin methylation and there are no compensatory mechanisms for CaM methylation in humans. We have further studied the expression of this gene at the transcript and protein levels. We have identified 2 additional transcripts in cells of the 2p21 deletion syndrome patients that start from alternative exons positioned outside the deletion region. One of them starts in the 2nd known exon, the other in a novel exon. The transcript starting from the novel exon was also identified in a variety of tissues from normal individuals. These new transcripts are not expected to produce proteins. Immunofluorescent localization of tagged CaM KMT in HeLa cells indicates that it is present in both the cytoplasm and nucleus of cells whereas the short isoform is localized to the Golgi apparatus. Using Western blot analysis we show that the CaM KMT protein is broadly expressed in mouse tissues. Finally we demonstrate that the CaM KMT interacts with the middle portion of the Hsp90 molecular chaperon and is probably a client protein since it is degraded upon treatment of cells with the Hsp90 inhibitor geldanamycin. These findings suggest that the CaM KMT is the major, possibly the single, methyltransferase of calmodulin in human cells with a wide tissue distribution and is a novel Hsp90 client protein. Thus our data provides basic information for a gene potentially contributing to the patient phenotype of two contiguous gene deletion syndromes.

show abstract

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

Cited by 45 publications

References 20 publications

Cystinuria: an inborn cause of urolithiasis

Cystinuria: an inborn cause of urolithiasis

Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice

Human Calmodulin Methyltransferase: Expression, Activity on Calmodulin, and Hsp90 Dependence

Contact Info

Product

Resources

About