The PERIOPTER syndrome ( perio rificial and pt ychotropic er ythrokeratoderma): a new Mendelian disorder of cornification

2018 ◽  
Vol 33 (1) ◽  
Author(s):  
A.‐C. Bursztejn ◽  
R. Happle ◽  
L. Charbit ◽  
J. Küsel ◽  
S. Leclerc‐Mercier ◽  
...  
Keyword(s):  
Mendelian Disorder ◽  
Disorder Of Cornification

scholarly journals Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Víctor Faundes ◽  
Martin D. Jennings ◽  
Siobhan Crilly ◽  
Sarah Legraie ◽  
Sarah E. Withers ◽  
...  
Keyword(s):  
De Novo ◽  
Model Systems ◽  
Yeast Growth ◽  
Related Disorder ◽  
Optimal Position ◽  
Human Phenotype ◽  
Mendelian Disorder ◽  
Growth Defects ◽  
Polysome Profiling

AbstractThe structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

scholarly journals RABENOSYN separation-of-function mutations uncouple endosomal recycling from lysosomal degradation

2021 ◽  
Author(s):  
Franziska Paul ◽  
Calista Ng ◽  
Shahriar Nafissi ◽  
Yalda Nilipoor ◽  
Ali Reza Tavasoli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Muscle Weakness ◽  
Germline Mutations ◽  
Lysosomal Degradation ◽  
Mendelian Disorder ◽  
Progressive Muscle Weakness ◽  
Endosomal Recycling ◽  
Early Endosomes ◽  
Recycling Pathway

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.

Embryo Genome Profiling by Single-Cell Sequencing for Preimplantation Genetic Diagnosis in a β-Thalassemia Family

2015 ◽  
Vol 61 (4) ◽  
pp. 617-626 ◽  
Author(s):  
Yanwen Xu ◽  
Shengpei Chen ◽  
Xuyang Yin ◽  
Xiaoting Shen ◽  
Xiaoyu Pan ◽  
...  
Keyword(s):  
Single Cell ◽  
Preimplantation Genetic Diagnosis ◽  
Genetic Diagnosis ◽  
Human Leukocyte ◽  
Nucleotide Polymorphisms ◽  
Clinical Practices ◽  
Mendelian Disorder ◽  
Leukocyte Antigen ◽  
Single Cell Sequencing ◽  
Embryonic Genome

Abstract BACKGROUND The embryonic genome, including genotypes and haplotypes, contains all the information for preimplantation genetic diagnosis, representing great potential for mendelian disorder carriers to conceive healthy babies. METHODS We developed a strategy to obtain the full embryonic genome for a β-thalassemia–carrier couple to have a healthy second baby. We carried out sequencing for single blastomere cells and the family trio and further developed the analysis pipeline, including recovery of the missing alleles, removal of the majority of errors, and phasing of the embryonic genome. RESULTS The final accuracy for homozygous and heterozygous single-nucleotide polymorphisms reached 99.62% and 98.39%, respectively. The aneuploidies of embryos were detected as well. Based on the comprehensive embryonic genome, we effectively performed whole-genome mendelian disorder diagnosis and human leukocyte antigen matching tests. CONCLUSIONS This retrospective study in a β-thalassemia family demonstrates a method for embryo genome recovery through single-cell sequencing, which permits detection of genetic variations in preimplantation genetic diagnosis. It shows the potential of single-cell sequencing technology in preimplantation genetic diagnosis clinical practices.

Reticular erythrokeratoderma: A new disorder of cornification

2003 ◽  
Vol 120A (2) ◽  
pp. 237-240 ◽  
Author(s):  
Peter H. Itin ◽  
Michael Moschopulos ◽  
Gabriela Richard
Keyword(s):  
Disorder Of Cornification

scholarly journals DPP9 deficiency : an Inflammasomopathy which can be rescued by lowering NLRP1/IL-1 signaling

2021 ◽  
Author(s):  
Cassandra R. Harapas ◽  
Kim S. Robinson ◽  
Kenneth Lay ◽  
Jasmine Wong ◽  
Annick Raas-Rothschild ◽  
...  
Keyword(s):  
Rare Variants ◽  
Skin Pigmentation ◽  
Single Copy ◽  
Neurological Deficits ◽  
Primary Cells ◽  
Loss Of Function ◽  
Mendelian Disorder ◽  
It Impacts ◽  
Biochemical Assays

AbstractDipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it impacts inflammasome regulation in vivo is not yet established. Here, we report two families with immune-associated defects, skin pigmentation abnormalities and neurological deficits that segregate with biallelic DPP9 rare variants. Using patient-derived primary cells and biochemical assays, these variants are shown to behave as hypomorphic or loss-of-function alleles that fail to repress NLRP1. Remarkably, the removal in mice, of a single copy of either Nlrp1a/b/c, Asc, Gsdmd, Il-1r, but not Il-18, was sufficient to rescue the lethality of Dpp9 mutant neonates. These experiments suggest that the deleterious consequences of DPP9 loss are mainly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in a mouse model of the disease.One Sentence SummaryLoss of DPP9 activity in humans and mice results in pathogenic NLRP1 overactivation.

scholarly journals Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis—Like Autosomal Recessive Congenital Ichthyosis

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258777
Author(s):  
Cherine Charfeddine ◽  
Nadia Laroussi ◽  
Rahma Mkaouar ◽  
Raja Jouini ◽  
Olfa Khayat ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Mutational Analysis ◽  
Clinical Phenotype ◽  
Homozygous Mutation ◽  
Congenital Ichthyosis ◽  
Whole Exome ◽  
Genes Encoding ◽  
Autosomal Recessive Congenital Ichthyosis ◽  
Connexin Genes ◽  
Disorder Of Cornification

Erythrokeratodermia variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3. Genetic heterogeneity of EKV has already been suggested. We investigated at the clinical and genetic level a consanguineous Tunisian family with 2 sisters presenting an autosomal recessive form of EKV to better characterize this disease. Mutational analysis initially screened the connexin genes and Whole-exome sequencing (WES) was performed to identify the molecular aetiology of the particular EKV phenotype in the proband. Migratory shaped erythematous areas are the initial presenting sign followed by relatively stable hyperkeratotic plaques are the two predominates characteristics in both patients. However, remarkable variability of morphological and dominating features of the disease were observed between patients. In particular, the younger sister (proband) exhibited ichthyosiform-like appearance suggesting Autosomal Recessive Congenital Ichthyosis (ARCI) condition. No causative mutations were detected in the GJB3 and GJB4 genes. WES results revealed a novel missense homozygous mutation in NIPAL4 gene (c.835C>G, p.Pro279Ala) in both patients. This variant is predicted to be likely pathogenic. In addition, in silico analysis of the mutated 3D domain structure predicted that this variant would result in NIPA4 protein destabilization and Mg2+ transport perturbation, pointing out the potential role of NIPAL4 gene in the development and maintenance of the barrier function of the epidermis. Taken togheter, these results expand the clinical phenotype associated with NIPAL4 mutation and reinforce our hypothesis of NIPAL4 as the main candidate gene for the EKV-like ARCI phenotype.

scholarly journals Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency

2020 ◽  
Vol 106 (2) ◽  
pp. 234-245 ◽  
Author(s):  
David B. Beck ◽  
Ana Petracovici ◽  
Chongsheng He ◽  
Hannah W. Moore ◽  
Raymond J. Louie ◽  
...  
Keyword(s):  
Dna Demethylation ◽  
Mendelian Disorder
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