Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3–p25.3

Kariminejad, Ariana; Nafissi, Shahriar; Nilipoor, Yalda; Tavasoli, Ali Reza; Veldhoven, Paul P. Van; Bonnard, Carine; Ng, Yeng Ting; Majoie, Charles B; Reversade, Bruno; Hennekam, Raoul C. M.

doi:10.1002/ajmg.a.37248

Cited by 8 publications

(15 citation statements)

References 15 publications

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“…It aligned with the gene TAMM41 ( TAM41 mitochondrial translocator assembly and maintenance homolog, Gene ID: 132001), which is a homolog of mitochondrial translocator assembly and maintenance protein. 32 , 33 …”

Section: Discussionmentioning

confidence: 99%

Profiles of differentially expressed circRNAs in esophageal and breast cancer

Shi¹,

Sun²,

He³

et al. 2018

CMAR

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IntroductionCircular RNAs (circRNAs) function as efficient microRNA sponges with gene-regulatory potential and are promising cancer biomarkers. In this study, we used the Arraystar Human circRNA Array to construct a genome-wide circRNA profile of esophageal squamous cell cancer (ESCC) and breast cancer (BC).Patients and methodsExpression levels between cancer lesions and adjacent normal-appearing tissues were compared. We observed 469 upregulated circRNAs and 275 downregulated circRNAs in ESCC. Hsa_circRNA_103670 was upregulated 20.3-fold, while hsa_circRNA_030162 was downregulated 12.1-fold. For BC, 715 circRNAs were upregulated, and 440 circRNAs were downregulated. Hsa_circRNA_005230 was upregulated 12.2-fold, while hsa_circRNA_406225 was downregulated 12.4-fold.ResultsWhen we set the criteria as fold change in expression ≥2 between cancer and adjacent normal-appearing tissue with a P-value <0.01, there were 22 common circRNAs (11 upregulated and 11 downregulated) in relation to both ESCC and BC. Gene ontology and the Kyoto encyclopedia of genes and genomes analyses showed that these circRNAs were involved in the tumorigenesis of human cancers.ConclusionOur study revealed that circRNAs are promising candidates as valuable biomarkers for ESCC and BC, although relevant research is still in its infancy and the functional role of specific circRNAs in tumorigenesis is just starting to be elucidated.

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Section: Discussionmentioning

confidence: 99%

Profiles of differentially expressed circRNAs in esophageal and breast cancer

Shi¹,

Sun²,

He³

et al. 2018

CMAR

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“…Mutations directly associated with the peroxisomal fatty acid α-oxidation pathway are extremely rare, with an estimated 1 in 10 6 incidence of Refsum disease in the UK [37], while only a handful of AMACR deficient patients have been reported in the literature. So far, there has been no definite report of a HACL1 deficient patient, although HACL1 was one of 57 candidate genes for a recessive syndrome involving intellectual disability, muscle weakness and a characteristic face [38]. However, we speculate that the alternative pathway activated in Hacl1 deficient mice may also be activated in humans, resulting in the lack of a clear peroxisomal metabolic disorder phenotype, hence the absence of an identified case.…”

Section: Discussionmentioning

confidence: 81%

Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation

Khalil

Carrino

Lin

et al. 2022

IJMS

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Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and Hacl1−/− mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the Hacl1−/− liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in Hacl1−/− mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1−/− mice in better understanding disease mechanism in fatty acid α-oxidation disorders.

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“…We have previously reported three siblings with a unique familial phenotype born to consanguineous healthy Red. parents (Kariminejad et al, 2015). Prominent characteristics include multiple neurological phenotypes, mild developmental delay and characteristic facial traits (Figures 1A-B, Figure EV1A-B).…”

Section: Resultsmentioning

confidence: 99%

“…The clinical history and pertinent data on the evaluation of the affected siblings, including results of linkage studies, have been published elsewhere (Kariminejad et al, 2015). Genomic DNA samples were collected from peripheral lymphocytes from the siblings and their parents.…”

Section: Methodsmentioning

confidence: 99%

RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation causing a distinct Mendelian Disorder

Paul

Nafissi

et al. 2021

Preprint

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Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively-acting germline alleles p.Arg180Gly and p.Gly183Arg which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate PI3P and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts exhibit accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.

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Intellectual disability, muscle weakness and characteristic face in three siblings: A newly described recessive syndrome mapping to 3p24.3–p25.3

Cited by 8 publications

References 15 publications

Profiles of differentially expressed circRNAs in esophageal and breast cancer

Profiles of differentially expressed circRNAs in esophageal and breast cancer

Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation

RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation causing a distinct Mendelian Disorder

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