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  1. AU="Weinberg-Shukron, Ariella"
  2. AU="Frost, Patrice A"
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  5. AU="Ziv Ben-Ari"
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  1. Article: Epigenetic control and genomic imprinting dynamics of the Dlk1-Dio3 domain.

    Weinberg-Shukron, Ariella / Youngson, Neil A / Ferguson-Smith, Anne C / Edwards, Carol A

    Frontiers in cell and developmental biology

    2023  Volume 11, Page(s) 1328806

    Abstract: Genomic imprinting is an epigenetic process whereby genes are monoallelically expressed in a parent-of-origin-specific manner. Imprinted genes are frequently found clustered in the genome, likely illustrating their need for both shared regulatory control ...

    Abstract Genomic imprinting is an epigenetic process whereby genes are monoallelically expressed in a parent-of-origin-specific manner. Imprinted genes are frequently found clustered in the genome, likely illustrating their need for both shared regulatory control and functional inter-dependence. The
    Language English
    Publishing date 2023-12-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2023.1328806
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Balanced gene dosage control rather than parental origin underpins genomic imprinting.

    Weinberg-Shukron, Ariella / Ben-Yair, Raz / Takahashi, Nozomi / Dunjić, Marko / Shtrikman, Alon / Edwards, Carol A / Ferguson-Smith, Anne C / Stelzer, Yonatan

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 4391

    Abstract: Mammalian parental imprinting represents an exquisite form of epigenetic control regulating the parent-specific monoallelic expression of genes in clusters. While imprinting perturbations are widely associated with developmental abnormalities, the ... ...

    Abstract Mammalian parental imprinting represents an exquisite form of epigenetic control regulating the parent-specific monoallelic expression of genes in clusters. While imprinting perturbations are widely associated with developmental abnormalities, the intricate regional interplay between imprinted genes makes interpreting the contribution of gene dosage effects to phenotypes a challenging task. Using mouse models with distinct deletions in an intergenic region controlling imprinting across the Dlk1-Dio3 domain, we link changes in genetic and epigenetic states to allelic-expression and phenotypic outcome in vivo. This determined how hierarchical interactions between regulatory elements orchestrate robust parent-specific expression, with implications for non-imprinted gene regulation. Strikingly, flipping imprinting on the parental chromosomes by crossing genotypes of complete and partial intergenic element deletions rescues the lethality of each deletion on its own. Our work indicates that parental origin of an epigenetic state is irrelevant as long as appropriate balanced gene expression is established and maintained at imprinted loci.
    MeSH term(s) Alleles ; Animals ; Chromosomes ; DNA Methylation/genetics ; DNA, Intergenic ; Gene Dosage ; Genomic Imprinting/genetics ; Mammals/genetics ; Mice
    Chemical Substances DNA, Intergenic
    Language English
    Publishing date 2022-07-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-32144-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Nucleoporin107 mediates female sexual differentiation via Dsx.

    Shore, Tikva / Levi, Tgst / Kalifa, Rachel / Dreifuss, Amatzia / Rekler, Dina / Weinberg-Shukron, Ariella / Nevo, Yuval / Bialistoky, Tzofia / Moyal, Victoria / Gold, Merav Yaffa / Leebhoff, Shira / Zangen, David / Deshpande, Girish / Gerlitz, Offer

    eLife

    2022  Volume 11

    Abstract: We recently identified a missense mutation in Nucleoporin107 (Nup107; D447N) underlying XX-ovarian-dysgenesis, a rare disorder characterized by underdeveloped and dysfunctional ovaries. Modeling of the human mutation ... ...

    Abstract We recently identified a missense mutation in Nucleoporin107 (Nup107; D447N) underlying XX-ovarian-dysgenesis, a rare disorder characterized by underdeveloped and dysfunctional ovaries. Modeling of the human mutation in
    MeSH term(s) Animals ; Aquaporins ; DNA-Binding Proteins/metabolism ; Drosophila/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Female ; Sex Differentiation/genetics
    Chemical Substances Aquaporins ; DNA-Binding Proteins ; DSX protein, Drosophila ; Drosophila Proteins ; Nup107 protein, Drosophila
    Language English
    Publishing date 2022-03-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.72632
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  4. Article: A Unique Presentation of XY Gonadal Dysgenesis in Frasier Syndrome due to WT1 Mutation and a Literature Review.

    Lavi, Eran / Zighan, Mahmud / Abu Libdeh, Abdulsalam / Klopstock, Tehila / Weinberg-Shukron, Ariella / Renbaum, Pinchas / Levy-Lahad, Ephrat / Zangen, David

    Pediatric endocrinology reviews : PER

    2020  Volume 17, Issue 4, Page(s) 302–307

    Abstract: Frasier syndrome (FS), a rare disease caused by inherited or de novo mutation in Wilm's Tumor suppressor gene 1 (WT1), is characterized by slow progressive nephropathy, XY gonadal dysgenesis (XY-DSD), and increased risk for gonadal tumors. Early ... ...

    Abstract Frasier syndrome (FS), a rare disease caused by inherited or de novo mutation in Wilm's Tumor suppressor gene 1 (WT1), is characterized by slow progressive nephropathy, XY gonadal dysgenesis (XY-DSD), and increased risk for gonadal tumors. Early childhood (1-6 years) nephropathy progresses with age to refractory nephrotic syndrome, and end-stage renal failure in late adolescence, when delayed puberty and/or primary amenorrhea are clinically evident. We report a unique case of FS presenting initially with primary amenorrhea at 16 years, without previous or concomitant renal damage. Only subsequently she developed an extremely late-onset nephropathy. Genetic analysis revealed the IVS9 + 5 G>A mutation in intron 9 of the WT1 gene. This clinical presentation and review of WT1 literature highlights the importance of considering FS in the differential diagnosis of patients with 46,XY disorders of Sexual development, even without nephropathy. Furthermore, the identification WT1 gene mutation prior to evident renal dysfunction indicates an immediate and close surveillance of renal function enabling an optimal and timely medical response.
    MeSH term(s) Child ; Child, Preschool ; Female ; Frasier Syndrome ; Gonadal Dysgenesis, 46,XY/genetics ; Gonadoblastoma ; Humans ; Infant ; Mutation ; Ovarian Neoplasms ; WT1 Proteins/genetics
    Chemical Substances WT1 Proteins ; WT1 protein, human
    Language English
    Publishing date 2020-08-11
    Publishing country Israel
    Document type Journal Article
    ZDB-ID 2434390-0
    ISSN 1565-4753
    ISSN 1565-4753
    DOI 10.17458/per.vol17.2020.lzz.xygonadalfrasiersyndromewt1mutation
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  5. Article ; Online: The novel R211Q POP1 homozygous mutation causes different pathogenesis and skeletal changes from those of previously reported POP1-associated anauxetic dysplasia.

    Abdulhadi-Atwan, Maha / Klopstock, Tehila / Sharaf, Muna / Weinberg-Shukron, Ariella / Renbaum, Paul / Levy-Lahad, Ephrat / Zangen, David

    American journal of medical genetics. Part A

    2020  Volume 182, Issue 5, Page(s) 1268–1272

    Abstract: Processing of Precursor RNA 1 (POP1) is a core protein component shared by two essential closely related eukaryotic ribonucleoprotein complexes: RNase MRP (the mitochondrial RNA processing ribonuclease) and RNase P. Recently, five patients harboring ... ...

    Abstract Processing of Precursor RNA 1 (POP1) is a core protein component shared by two essential closely related eukaryotic ribonucleoprotein complexes: RNase MRP (the mitochondrial RNA processing ribonuclease) and RNase P. Recently, five patients harboring mutations in POP1 have been reported with severe spondylo-epi-metaphyseal dysplasia and extremely short stature. We report a unique clinical phenotype resulting from the novel homozygous R211Q POP1 mutation in three patients from one family, presenting with severe short stature but only subtle skeletal dysplastic changes that are merely metaphyseal. The RNA moiety of the RNase-MRP complex quantified in RNA extracted from peripheral lymphocytes was dramatically reduced in affected patients indicating instability of the enzymatic complex. However, pre5.8s rRNA, a substrate of RNase-MRP complex, was not accumulated in patients' RNA unlike in the previously reported POP1 mutations; this may explain the uniquely mild phenotype in our cases, and questions the assumption that alteration in ribosomal biogenesis is the pathophysiological basis for skeletal disorders caused by POP1 mutations. Finally, POP1 mutations should be considered in familial cases with severe short stature even when skeletal dysplasia is not strongly evident.
    MeSH term(s) Apoptosis Regulatory Proteins/genetics ; Child ; Consanguinity ; Dwarfism/diagnostic imaging ; Dwarfism/genetics ; Dwarfism/pathology ; Genetic Predisposition to Disease ; Homozygote ; Humans ; Male ; Muscle, Skeletal/diagnostic imaging ; Muscle, Skeletal/pathology ; Musculoskeletal Abnormalities ; Mutation/genetics ; Osteochondrodysplasias/diagnostic imaging ; Osteochondrodysplasias/genetics ; Osteochondrodysplasias/pathology ; RNA Precursors/genetics ; Ribonucleoproteins/genetics ; Ribosomes/genetics
    Chemical Substances Apoptosis Regulatory Proteins ; POP1 protein, human ; RNA Precursors ; Ribonucleoproteins
    Language English
    Publishing date 2020-03-05
    Publishing country United States
    Document type Case Reports
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.61538
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  6. Article ; Online: NKX2-2 Mutation Causes Congenital Diabetes and Infantile Obesity With Paradoxical Glucose-Induced Ghrelin Secretion.

    Auerbach, Adi / Cohen, Amitay / Ofek Shlomai, Noa / Weinberg-Shukron, Ariella / Gulsuner, Suleyman / King, Mary-Claire / Hemi, Rina / Levy-Lahad, Ephrat / Abulibdeh, Abdulsalam / Zangen, David

    The Journal of clinical endocrinology and metabolism

    2020  Volume 105, Issue 11

    Abstract: Context: NKX2-2 is a crucial transcription factor that enables specific β-cell gene expression. Nkx2-2(-/-) mice manifest with severe neonatal diabetes and changes in β-cell progenitor fate into ghrelin-producing cells. In humans, recessive NKX2-2 gene ... ...

    Abstract Context: NKX2-2 is a crucial transcription factor that enables specific β-cell gene expression. Nkx2-2(-/-) mice manifest with severe neonatal diabetes and changes in β-cell progenitor fate into ghrelin-producing cells. In humans, recessive NKX2-2 gene mutations have been recently reported as a novel etiology for neonatal diabetes, with only 3 cases known worldwide. This study describes the genetic analysis, distinctive clinical features, the therapeutic challenges, and the unique pathophysiology causing neonatal diabetes in human NKX2-2 dysfunction.
    Case description: An infant with very low birth weight (VLBW) and severe neonatal diabetes (NDM) presented with severe obesity and developmental delay already at age 1 year. The challenge of achieving glycemic control in a VLBW infant was unexpectedly met by a regimen of 3 daily doses of long-acting insulin analogues. Sanger sequencing of known NDM genes (such as ABCC8 and EIF2AK3) was followed by whole-exome sequencing that revealed homozygosity of a pathogenic frameshift variant, c.356delG, p.P119fs64*, in the islet cells transcription factor, NKX2-2. To elucidate the cause for the severe obesity, an oral glucose tolerance test was conducted at age 3.5 years and revealed undetectable C-peptide levels with a paradoxically unexpected 30% increase in ghrelin levels.
    Conclusion: Recessive NKX2-2 loss of function causes severe NDM associated with VLBW, childhood obesity, and developmental delay. The severe obesity phenotype is associated with postprandial paradoxical ghrelin secretion, which may be related to human β-cell fate change to ghrelin-secreting cells, recapitulating the finding in Nkx2-2(-/-) mice islet cells.
    MeSH term(s) Child, Preschool ; Diabetes Mellitus/genetics ; Diabetes Mellitus/metabolism ; Female ; Ghrelin/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Infant ; Infant, Very Low Birth Weight ; Mutation ; Pediatric Obesity/genetics ; Pediatric Obesity/metabolism ; Whole Exome Sequencing ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Ghrelin ; Homeodomain Proteins ; Nkx2.2 protein ; Zebrafish Proteins
    Language English
    Publishing date 2020-08-14
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/clinem/dgaa563
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  7. Article ; Online: Essential Role of BRCA2 in Ovarian Development and Function.

    Weinberg-Shukron, Ariella / Rachmiel, Mariana / Renbaum, Paul / Gulsuner, Suleyman / Walsh, Tom / Lobel, Orit / Dreifuss, Amatzia / Ben-Moshe, Avital / Zeligson, Sharon / Segel, Reeval / Shore, Tikva / Kalifa, Rachel / Goldberg, Michal / King, Mary-Claire / Gerlitz, Offer / Levy-Lahad, Ephrat / Zangen, David

    The New England journal of medicine

    2018  Volume 379, Issue 11, Page(s) 1042–1049

    Abstract: The causes of ovarian dysgenesis remain incompletely understood. Two sisters with XX ovarian dysgenesis carried compound heterozygous truncating mutations in the BRCA2 gene that led to reduced BRCA2 protein levels and an impaired response to DNA damage, ... ...

    Abstract The causes of ovarian dysgenesis remain incompletely understood. Two sisters with XX ovarian dysgenesis carried compound heterozygous truncating mutations in the BRCA2 gene that led to reduced BRCA2 protein levels and an impaired response to DNA damage, which resulted in chromosomal breakage and the failure of RAD51 to be recruited to double-stranded DNA breaks. The sisters also had microcephaly, and one sister was in long-term remission from leukemia, which had been diagnosed when she was 5 years old. Drosophila mutants that were null for an orthologue of BRCA2 were sterile, and gonadal dysgenesis was present in both sexes. These results revealed a new role for BRCA2 and highlight the importance to ovarian development of genes that are critical for recombination during meiosis. (Funded by the Israel Science Foundation and others.).
    MeSH term(s) Adolescent ; Animals ; BRCA2 Protein/deficiency ; BRCA2 Protein/physiology ; Chromosome Breakage/drug effects ; DNA Mutational Analysis ; DNA Repair ; Drosophila melanogaster ; Female ; Genes, BRCA2 ; Gonadal Dysgenesis/genetics ; Humans ; Hypogonadism/genetics ; Male ; Microcephaly/genetics ; Mitomycin/pharmacology ; Models, Animal ; Ovary/growth & development ; Ovary/physiology ; Pedigree ; Siblings ; Young Adult
    Chemical Substances BRCA2 Protein ; BRCA2 protein, human ; Mitomycin (50SG953SK6)
    Language English
    Publishing date 2018-09-12
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMoa1800024
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  8. Article ; Online: Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome.

    Aran, Adi / Segel, Reeval / Kaneshige, Kota / Gulsuner, Suleyman / Renbaum, Paul / Oliphant, Scott / Meirson, Tomer / Weinberg-Shukron, Ariella / Hershkovitz, Yair / Zeligson, Sharon / Lee, Ming K / Samson, Abraham O / Parsons, Stanley M / King, Mary-Claire / Levy-Lahad, Ephrat / Walsh, Tom

    Neurology

    2017  Volume 88, Issue 11, Page(s) 1021–1028

    Abstract: Objective: To identify the genetic basis of a recessive congenital neurologic syndrome characterized by severe hypotonia, arthrogryposis, and respiratory failure.: Methods: Identification of the responsible gene by exome sequencing and assessment of ... ...

    Abstract Objective: To identify the genetic basis of a recessive congenital neurologic syndrome characterized by severe hypotonia, arthrogryposis, and respiratory failure.
    Methods: Identification of the responsible gene by exome sequencing and assessment of the effect of the mutation on protein stability in transfected rat neuronal-like PC12
    Results: Two brothers from a nonconsanguineous Yemeni Jewish family manifested at birth with severe hypotonia and arthrogryposis. The older brother died of respiratory failure at 5 days of age. The proband, now 4.5 years old, has been mechanically ventilated since birth with virtually no milestones achievement. Whole exome sequencing revealed homozygosity of
    Conclusion: Loss of function of VAChT underlies severe arthrogryposis and respiratory failure. While most congenital myasthenic syndromes are caused by defects in postsynaptic proteins, VAChT deficiency is a presynaptic myasthenic syndrome.
    MeSH term(s) Adult ; Animals ; Arginine/genetics ; Family Health ; Glycine/genetics ; Humans ; Male ; Mice ; Mice, Transgenic ; Mutation/genetics ; Myasthenic Syndromes, Congenital/complications ; Myasthenic Syndromes, Congenital/genetics ; Myasthenic Syndromes, Congenital/metabolism ; PC12 Cells ; Protein Processing, Post-Translational/genetics ; RNA, Messenger ; Rats ; Transfection ; Vesicular Acetylcholine Transport Proteins/genetics ; Vesicular Acetylcholine Transport Proteins/metabolism
    Chemical Substances RNA, Messenger ; Vesicular Acetylcholine Transport Proteins ; Arginine (94ZLA3W45F) ; Glycine (TE7660XO1C)
    Language English
    Publishing date 2017-02-10
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 207147-2
    ISSN 1526-632X ; 0028-3878
    ISSN (online) 1526-632X
    ISSN 0028-3878
    DOI 10.1212/WNL.0000000000003720
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  9. Article ; Online: Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations.

    Zeevi, David A / Altarescu, Gheona / Weinberg-Shukron, Ariella / Zahdeh, Fouad / Dinur, Tama / Chicco, Gaya / Herskovitz, Yair / Renbaum, Paul / Elstein, Deborah / Levy-Lahad, Ephrat / Rolfs, Arndt / Zimran, Ari

    The Journal of clinical investigation

    2015  Volume 125, Issue 10, Page(s) 3757–3765

    Abstract: Background: Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of ... ...

    Abstract Background: Noninvasive prenatal testing can be used to accurately detect chromosomal aneuploidies in circulating fetal DNA; however, the necessity of parental haplotype construction is a primary drawback to noninvasive prenatal diagnosis (NIPD) of monogenic disease. Family-specific haplotype assembly is essential for accurate diagnosis of minuscule amounts of circulating cell-free fetal DNA; however, current haplotyping techniques are too time-consuming and laborious to be carried out within the limited time constraints of prenatal testing, hampering practical application of NIPD in the clinic. Here, we have addressed this pitfall and devised a universal strategy for rapid NIPD of a prevalent mutation in the Ashkenazi Jewish (AJ) population.
    Methods: Pregnant AJ couples, carrying mutation(s) in GBA, which encodes acid β-glucosidase, were recruited at the SZMC Gaucher Clinic. Targeted next-generation sequencing of GBA-flanking SNPs was performed on peripheral blood samples from each couple, relevant mutation carrier family members, and unrelated individuals who are homozygotes for an AJ founder mutation. Allele-specific haplotypes were constructed based on linkage, and a consensus Gaucher disease-associated founder mutation-flanking haplotype was fine mapped. Together, these haplotypes were used for NIPD. All test results were validated by conventional prenatal or postnatal diagnostic methods.
    Results: Ten parental alleles in eight unrelated fetuses were diagnosed successfully based on the noninvasive method developed in this study. The consensus mutation-flanking haplotype aided diagnosis for 6 of 9 founder mutation alleles.
    Conclusions: The founder NIPD method developed and described here is rapid, economical, and readily adaptable for prenatal testing of prevalent autosomal recessive disease-causing mutations in an assortment of worldwide populations.
    Funding: SZMC, Protalix Biotherapeutics Inc., and Centogene AG.
    MeSH term(s) Alleles ; Consensus Sequence ; DNA/blood ; DNA/genetics ; DNA Mutational Analysis ; Early Diagnosis ; Female ; Fetal Diseases/diagnosis ; Fetal Diseases/genetics ; Fetomaternal Transfusion ; Founder Effect ; Gaucher Disease/diagnosis ; Gaucher Disease/embryology ; Gaucher Disease/genetics ; Genes, Recessive ; Glucosylceramidase/genetics ; Haplotypes ; Humans ; Jews/genetics ; Pedigree ; Polymorphism, Single Nucleotide ; Pregnancy ; Prenatal Diagnosis/methods ; Sensitivity and Specificity ; Sequence Analysis, DNA ; Time Factors
    Chemical Substances DNA (9007-49-2) ; Glucosylceramidase (EC 3.2.1.45)
    Language English
    Publishing date 2015-10-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Validation Studies
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI79322
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  10. Article ; Online: Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress.

    Weinberg-Shukron, Ariella / Abu-Libdeh, Abdulsalam / Zhadeh, Fouad / Carmel, Liran / Kogot-Levin, Aviram / Kamal, Lara / Kanaan, Moien / Zeligson, Sharon / Renbaum, Paul / Levy-Lahad, Ephrat / Zangen, David

    Journal of medical genetics

    2015  Volume 52, Issue 9, Page(s) 636–641

    Abstract: Background: Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, ... ...

    Abstract Background: Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.
    Methods and results: In a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects.
    Conclusions: This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.
    MeSH term(s) Arabs ; Consanguinity ; Glucocorticoids/deficiency ; Homozygote ; Humans ; Mineralocorticoids/deficiency ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mutation ; NADP Transhydrogenases/genetics ; Oxidative Stress/genetics ; Receptors, Mineralocorticoid/metabolism ; Sequence Analysis, DNA
    Chemical Substances Glucocorticoids ; Mineralocorticoids ; Receptors, Mineralocorticoid ; NADP Transhydrogenases (EC 1.6.1.-)
    Language English
    Publishing date 2015-09
    Publishing country England
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmedgenet-2015-103078
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