Two novel deletions in hypotonia–cystinuria syndrome

Régal, Luc; Aydin, Halil İbrahim; Dieltjens, Anne-Marie; Esch, Hilde Van; François, Inge; Okur, İlyas; Zeybek, Cengiz; Meulemans, Sandra; Mol, Christine Van; Bruwaene, Lore Van; Then, Siao-Hann; Jaeken, Jaak; Creemers, John W.M.

doi:10.1016/j.ymgme.2012.06.011

Cited by 15 publications

(18 citation statements)

References 10 publications

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“…41 Deletions that were limited to SLC3A1 and PREPL showed no reduction in OXPHOS activity, with the exception of a single patient out of a group of 22 who showed a reduction in complex V activity. [42][43][44][45][46] Patients with a deletion encompassing only PREPL and CAMKMT showed elevated lactate and hypotonia, suggesting mitochondrial involvement, but OXPHOS enzyme activity were not measured. 42 When assessing combinations of deletions and the corresponding OXPHOS enzyme characterization that has been published, our deduction indicates that of the 4 genes that are involved in the 2p21 deletion syndrome, a deletion of CAMKMT is present in most of the patients in which a mitochondrial phenotype has also been observed, suggesting that this gene is responsible for the mitochondrial connection with this syndrome.…”

Section: Dravet Syndrome (Scn1a)mentioning

confidence: 99%

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Panneman¹,

Smeitink²,

Rodenburg³

2017

Clinical Genetics

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Mitochondrial disorders (MDs) are caused by defects in 1 or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non-mitochondrial syndromes. Here, we give an overview of around 25 non-mitochondrial syndromes, diagnosed in patients who were initially suspected to have a MD on the basis of clinical and biochemical parameters. In addition, we highlight the mitochondrial connections of 6 of these non-mitochondrial syndromes (eg, Rett syndrome and Dravet syndrome) diagnosed in multiple patients. Further research to unravel the interplay between these genes and mitochondria may help to increase knowledge on these syndromes. Additionally, it may open new avenues for research on pathways interacting with mitochondrial function in order to find new targets for therapeutics to treat MDs. The data presented in this review underline the importance of careful assessment of clinical, genetic, and biochemical data in all patients suspected of a neuromuscular syndrome, and highlights the importance of the role of clinical geneticists, physicians, and clinical biochemists in recognizing the possible mitochondrial connection of non-mitochondrial syndromes.

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Section: Dravet Syndrome (Scn1a)mentioning

confidence: 99%

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Panneman¹,

Smeitink²,

Rodenburg³

2017

Clinical Genetics

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“…Interest in the prolyl endopeptidase-like gene ( PREPL ) was sparked by the discovery that this gene associated with 2p21 deletion syndrome [1], [2] and also with hypotonia-cystinuria syndrome (HCS) [3]–[5]. HCS presents clinically as decreased muscle tone (hypotonia) as well as excess cystine in the urine (cystinuria), but other symptoms such as diminished growth and mild mental retardation are also associated with HCS.…”

Section: Introductionmentioning

confidence: 99%

Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice

et al. 2014

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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.

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“…Hypotonia‐cystinuria syndrome (HCS, MIM606407) is characterized by severe infantile hypotonia, poor feeding, and growth hormone deficiency. Affected individuals carry homozygous deletions encompassing the SLC3A1 and PREPL genes [Zaffanello et al, ; Jaeken et al, ; Martens et al, ; Régal et al, ; Eggermann et al, ]. 2p21 deletion syndrome, in addition to the features of HCS, is characterized by neonatal seizures, elevated serum lactate concentrations and developmental delay.…”

Section: Introductionmentioning

confidence: 99%

Further delineation of genotype–phenotype correlation in homozygous 2p21 deletion syndromes: First description of patients without cystinuria

Bartholdi

Asadollahi

Oneda

et al. 2013

American J of Med Genetics Pt A

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Homozygous contiguous gene deletion syndromes are rare. On 2p21, however, several overlapping homozygous gene deletion syndromes have been described, all presenting with cystinuria but otherwise distinct phenotypes. Hypotonia-cystinuria syndrome (HCS, OMIM606407) is characterized by infantile hypotonia, poor feeding, and growth hormone deficiency. Affected individuals carry homozygous deletions including the cystinuria gene SLC3A1 and the adjacent PREPL gene. Larger homozygous deletions in this region encompassing the PPM1B, SLC3A1, PREPL, and C2orf34 (CAMKMT) genes result in a more severe phenotype, the 2p21 deletion syndrome. A phenotype intermediate to HCS and the 2p21 deletion syndrome is termed atypical HCS and is caused by deletion of SLC3A1, PREPL, and C2orf34 (CAMKMT). Using high resolution SNP array molecular karyotyping we identified two siblings with a homozygous deletion of 83 kb partially encompassing the genes PREPL and C2orf34 (CAMKMT), but not the SLC3A1 gene. The affected siblings display a recognizable phenotype which is similar to atypical HCS with regard to growth failure and neuro-muscular features, but is characterized by lack of cystinuria. The patients also exhibit features which have not been reported to date such as cleft palate and genital abnormalities. In conclusion, we report the first patients with a homozygous 2p21 deletion syndrome without cystinuria and further delineate the complex genotype-phenotype correlations of homozygous microdeletion syndromes of this region.

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Two novel deletions in hypotonia–cystinuria syndrome

Cited by 15 publications

References 10 publications

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Mining for mitochondrial mechanisms: Linking known syndromes to mitochondrial function

Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice

Further delineation of genotype–phenotype correlation in homozygous 2p21 deletion syndromes: First description of patients without cystinuria

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