scholarly journals Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality

2020 ◽  
pp. jmedgenet-2020-106873
Author(s):  
Marilena Elpidorou ◽  
Sunayna Best ◽  
James A Poulter ◽  
Verity Hartill ◽  
Emma Hobson ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Stop Codon ◽  
Neurodevelopmental Disorder ◽  
Premature Stop Codon ◽  
Homozygous Deletion ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Functional Characterisation ◽  
Mitochondrial Functions ◽  
And Function

BackgroundThe HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype.Methods and resultsWe ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA.ConclusionThis study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders.

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals Cis-Segregation of c.1171C>T Stop Codon (p.R391*) in SERPINC1 Gene and c.1691G>A Transition (p.R506Q) in F5 Gene and Selected GWAS Multilocus Approach in Inherited Thrombophilia

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 934
Author(s):  
Donato Gemmati ◽  
Giovanna Longo ◽  
Eugenia Franchini ◽  
Juliana Araujo Silva ◽  
Ines Gallo ◽  
...  
Keyword(s):  
At Risk ◽  
Stop Codon ◽  
Association Studies ◽  
Premature Stop Codon ◽  
Large Family ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Gene Markers ◽  
Inherited Thrombophilia ◽  
Fv Leiden

Inherited thrombophilia (e.g., venous thromboembolism, VTE) is due to rare loss-of-function mutations in anticoagulant factors genes (i.e., SERPINC1, PROC, PROS1), common gain-of-function mutations in procoagulant factors genes (i.e., F5, F2), and acquired risk conditions. Genome Wide Association Studies (GWAS) recently recognized several genes associated with VTE though gene defects may unpredictably remain asymptomatic, so calculating the individual genetic predisposition is a challenging task. We investigated a large family with severe, recurrent, early-onset VTE in which two sisters experienced VTE during pregnancies characterized by a perinatal in-utero thrombosis in the newborn and a life-saving pregnancy-interruption because of massive VTE, respectively. A nonsense mutation (CGA > TGA) generating a premature stop-codon (c.1171C>T; p.R391*) in the exon 6 of SERPINC1 gene (1q25.1) causing Antithrombin (AT) deficiency and the common missense mutation (c.1691G>A; p.R506Q) in the exon 10 of F5 gene (1q24.2) (i.e., FV Leiden; rs6025) were coinherited in all the symptomatic members investigated suspecting a cis-segregation further confirmed by STR-linkage-analyses [i.e., SERPINC1 IVS5 (ATT)5–18, F5 IVS2 (AT)6–33 and F5 IVS11 (GT)12–16] and SERPINC1 intragenic variants (i.e., rs5878 and rs677). A multilocus investigation of blood-coagulation balance genes detected the coexistence of FV Leiden (rs6025) in trans with FV HR2-haplotype (p.H1299R; rs1800595) in the aborted fetus, and F11 rs2289252, F12 rs1801020, F13A1 rs5985, and KNG1 rs710446 in the newborn and other members. Common selected gene variants may strongly synergize with less common mutations tuning potential life-threatening conditions when combined with rare severest mutations. Merging classic and newly GWAS-identified gene markers in at risk families is mandatory for VTE risk estimation in the clinical practice, avoiding partial risk score evaluation in unrecognized at risk patients.

scholarly journals ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

Neurogenetics ◽  
2021 ◽  
Author(s):  
Katja Kloth ◽  
Bernarda Lozic ◽  
Julia Tagoe ◽  
Mariëtte J. V. Hoffer ◽  
Amelie Van der Ven ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Neuronal Development ◽  
Autosomal Dominant ◽  
Tissue Expression ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Ankyrin G ◽  
Phenotypic Spectrum ◽  
And Function ◽  
Neurodevelopmental Phenotype

AbstractANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.

scholarly journals DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

2019 ◽  
Vol 116 (50) ◽  
pp. 25322-25328 ◽  
Author(s):  
Yi Liu ◽  
Xiaopin Ma ◽  
Hisashi Fujioka ◽  
Jun Liu ◽  
Shengdi Chen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cellular Mechanism ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Efflux ◽  
And Function ◽  
The Brain ◽  
Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

scholarly journals Loss-of-function in IRF2BPL is associated with neurological phenotypes

2018 ◽  
Author(s):  
Paul C. Marcogliese ◽  
Vandana Shashi ◽  
Rebecca C. Spillmann ◽  
Nicholas Stong ◽  
Jill A. Rosenfeld ◽  
...  
Keyword(s):  
Nervous System ◽  
Population Genomics ◽  
Stop Codon ◽  
Ectopic Expression ◽  
Premature Stop Codon ◽  
Model Organism ◽  
Global Developmental Delay ◽  
Mendelian Disease ◽  
Loss Of Function ◽  
Missense Variants

AbstractThe Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) gene encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals affected with neurological symptoms who carry damaging heterozygous variants in IRF2BPL. Five cases carrying nonsense variants in IRF2BPL resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The bioinformatics signature for IRF2BPL based on population genomics is consistent with a gene that is intolerant to variation. We show that the IRF2BPL ortholog in the fruit fly, called pits (protein interacting with Ttk69 and Sin3A), is broadly expressed including the nervous system. Complete loss of pits is lethal early in development, whereas partial knock-down with RNA interference in neurons leads to neurodegeneration, revealing requirement for this gene in proper neuronal function and maintenance. The nonsense variants in IRF2BPL identified in patients behave as severe loss-of-function alleles in this model organism, while ectopic expression of the missense variants leads to a range of phenotypes. Taken together, IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

Mutations of TET2 and JAK2 but Not CBL Are Detectable in a High Portion of Patients with Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1766-1766
Author(s):  
Johanna Flach ◽  
Sonja Schindela ◽  
Frank Dicker ◽  
Susanne Schnittger ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Stop Codon ◽  
Myeloproliferative Neoplasms ◽  
Premature Stop Codon ◽  
Jak2v617f Mutation ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Myeloid Malignancies ◽  
Ring Sideroblasts ◽  
Equity Ownership

Abstract Abstract 1766 Poster Board I-792 Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) forms a provisional entity within the category of MDS/MPN-U in the 2008 WHO classification. Although the identification of the JAK2V617F mutation was an important first step in distinguishing this entity from other hematological diseases, further genetic characterization is necessary. We performed comprehensive cytogenetic and molecular genetic investigations including targeted analysis of JAK2V617F, TET2, MPLW515 and CBL, markers known to be altered in MPN, as well as genome-wide single nucleotide polymorphism microarray analysis (SNP-A) in 23 RARS-T patients who fulfilled WHO 2008 diagnostic criteria. The JAK2V617F mutation was detectable in 15 out of 19 analyzed patients (78.9%), four of which were homozygous. However, our patients neither carried a MPLW515 mutation nor mutations in exons 8 or 9 of CBL genes. These genes were recently described to be mainly mutated in myeloproliferative neoplasms. In addition, conventional cytogenetic analysis did not reveal any recurrent cytogenetic abnormalities in RARS-T patients. We also performed SNP microarray analysis in a subset of 10 RARS-T patients. Although we did neither observe recurrent chromosomal gains or losses nor recurring regions of UPD, one patient showed a deletion spanning a 1.3 Mb region on the long arm of chromosome 4 (start: 105,497,200 bp from pter; end: 106,825,780 bp from pter). The deleted region contained TET2, a gene recently found to be altered in many subtypes of myeloid malignancies. To further clarify the 4q24 deletion detected by SNP-A analysis we performed fluorescence in situ hybridization (FISH). 20 out of 100 analyzed interphase nuclei and three metaphases showed only one signal for the probe spanning the TET2 gene in this patient. Interphase FISH with the TET2 probe was performed in nine additional cases not analyzed by SNP arrays due to a lack of material, but no additional case showing a deletion was detected. In addition to FISH, we performed TET2 sequencing in 19/23 RARS-T patients. TET2 mutations were detected in 5/19 patients (26%), of which 3/5 also presented the JAK2V617F mutation, whereas the remaining 2/5 did neither show JAK2V617F nor MPL nor CBL mutations. The five patients showed 6 individually different TET2 mutations. Three were nonsense and two missense mutations. One patient displayed a frameshift mutation leading to a premature stop codon. In summary, RARS-T patients demonstrated a high frequency of both JAK2 and TET2 mutations. Together with the less common MPL mutations described by others RARS-T presents a variety of mutations that overlap with the spectrum of mutations seen in MPN and other myeloid malignancies. Thus, a combination of molecular markers including JAK2 and TET2 should be investigated to more precisely describe RARS-T as an independent disease entity. Disclosures Flach: MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Weiss:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

An Autosomal-Recessive GFI1B Mutation Defines the Splice Isoform p37 As Essential for Biogenesis of Functional Human Platelets, but Dispensable for Erythropoiesis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2644-2644
Author(s):  
Harald Schulze ◽  
Axel Schlagenhauf ◽  
Georgi Manukjan ◽  
Christine Beham-Schmid ◽  
Oliver Andres ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Growth Factor ◽  
Autosomal Recessive ◽  
Stop Codon ◽  
Zinc Fingers ◽  
Premature Stop Codon ◽  
Index Patient ◽  
Homozygous Mutation ◽  
Recessive Trait ◽  
Erythroid Progenitor

Abstract Growth factor independent 1 (GFI1) and Growth Factor Independent 1B (GFI1B) are zinc finger transcriptional repressors that share about 90% homology on amino acid sequence and are expressed during hematopoiesis. While GFI1 is most important for granulocyte-monocyte lineage commitment, GFI1B is an essential master regulator of erythroid and megakaryocytic lineages. Mice lacking Gfi1b are embryonic lethal due to anemia and thrombocytopenia. In humans, alternative splicing leads to a shorter p32 isoform that lacks the first 2 of 6 zinc fingers. GFI1B germline mutations have been reported to cause autosomal-dominant macrothrombocytopenia with a grey-platelet syndrome phenotype, implying that the mutant protein acts in a dominant-negative manner. We report on a Chechen family from eastern Georgia whose affected family members all present with severe, life-threatening bleeding diathesis. The female index patient had recurrent hematomata and multiple petechiae since childhood. Both of her children (age 9 and 7) present with very low platelet counts (below 45/nL) and a similar cutaneous bleeding pattern like her mother. The brother also had thrombocytopenia and died at age 33 in reponse to a spontaneous cerebral hemorrhage. In contrast, the index patient's husband, her parents and the children of the deceased brother were clinically unaffected. Blood smears of affected patients showed macrothrombocytopenia with reduced May-Grünwald-Giema staining and decreased staining for alpha-granule markers von Willebrand factor (vWF) and P-selectin (CD62P). Platelet function testing revealed reduced responses to ADP, collagen, TRAP-6 and arachidonic acid. White and red blood cell parameters were overall normal in the index patient and the two affected children. We analyzed DNA from the index patient by targeted next generation sequencing for 59 genes relevant for platelet formation or function. We found a novel homozygous single nucleotide insertion in GFI1B (NM_004188.5; c.551insG), which was confirmed by Sanger sequencing and is expected to cause a premature stop-codon. The homozygous mutation co-segregated with the phenotype. The unaffected mother, the husband and two unaffected nephews were heterozygous, suggesting a local founder variant and an unexpected autosomal-recessive trait. Bone marrow analysis showed unaffected myeloid and erythroid cells, but dysplastic micromegakaryocytes with increased CD34 staining. Peripheral blood platelets were also positive for CD34. We performed quantitative real-time PCR of platelet RNA and found residual homozygous c.551_G insertion in the p37 transcript and an unexpected expression of the p32 variant. The p37 transcript was markedly reduced in context with an increased p32/p37 ratio compared to controls. Our findings indicate that the mutated transcript was not completely degraded by nonsense-mediated decay, but mostly subjected to alternative splicing skipping the mutated exon 9. Our findings imply that the first two zinc fingers of GFI1B are dispensable for human erythropoiesis, but essential for normal megakaryopoiesis and the production of functional platelets. While previous mutations affect both isoforms, the insertion variant presented here, results in a premature stop-codon and affects only the p37 isoform due to alternative splicing. This splice variant defines an important node at the megakaryocytic-erythroid progenitor stage and we conclude that the transcriptional regulation of erythropoiesis is uncoupled from that of megakaryopoiesis through alternative splicing of GFI1B. Disclosures No relevant conflicts of interest to declare.

scholarly journals Premature Stop Codon in MMP20 Causing Amelogenesis Imperfecta

2008 ◽  
Vol 87 (1) ◽  
pp. 56-59 ◽  
Author(s):  
P. Papagerakis ◽  
H.-K. Lin ◽  
K.Y. Lee ◽  
Y. Hu ◽  
J.P. Simmer ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Proteolytic Enzymes ◽  
Stop Codon ◽  
Translation Termination ◽  
Premature Stop Codon ◽  
Dental Enamel ◽  
Amino Acid Position ◽  
Amelogenesis Imperfecta ◽  
Exon 1 ◽  
Kallikrein 4

Proteolytic enzymes are necessary for the mineralization of dental enamel during development, and mutations in the kallikrein 4 ( KLK4) and enamelysin ( MMP20) genes cause autosomal-recessive amelogenesis imperfecta (ARAI). So far, only one KLK4 and two MMP20 mutations have been reported. We have identified an ARAI-causing point mutation (c.102G>A, g.102G>A, and p.W34X) in exon 1 of MMP20 in a proband with autosomal-recessive hypoplastic-hypomaturation amelogenesis imperfecta. The G to A transition changes the tryptophan (W) codon (TGG) at amino acid position 34 into a translation termination (X) codon (TGA). No disease-causing sequence variations were detected in KLK4. The affected enamel is thin, with mild spacing in the anterior dentition. The enamel layer is hypomineralized, does not contrast with dentin on radiographs, and tends to chip away from the underlying dentin. An intrinsic yellowish pigmentation is evident, even during eruption. The phenotype supports current ideas concerning the function of enamelysin.

scholarly journals Synergistic Activation of Defense Responses in Arabidopsis by Simultaneous Loss of the GSL5 Callose Synthase and the EDR1 Protein Kinase

2010 ◽  
Vol 23 (5) ◽  
pp. 578-584 ◽  
Author(s):  
Anna Wawrzynska ◽  
Natalie L. Rodibaugh ◽  
Roger W. Innes
Keyword(s):  
Powdery Mildew ◽  
Positional Cloning ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Defense Responses ◽  
Loss Of Function ◽  
Callose Synthase ◽  
Synergistic Activation ◽  
Golovinomyces Cichoracearum ◽  
Inducible Gene

Loss-of-function mutations in the EDR1 gene of Arabidopsis confer enhanced resistance to Golovinomyces cichoracearum (powdery mildew). Disease resistance mediated by the edr1 mutation is dependent on an intact salicylic acid (SA) signaling pathway, but edr1 mutant plants do not constitutively express the SA-inducible gene PR-1 and are not dwarfed. To identify other components of the EDR1 signaling network, we screened for mutations that enhanced the edr1 mutant phenotype. Here, we describe an enhancer of edr1 mutant, eed3, which forms spontaneous lesions in the absence of pathogen infection, constitutively expresses both SA- and methyl jasmonate (JA)–inducible defense genes, and is dwarfed. Positional cloning of eed3 revealed that the mutation causes a premature stop codon in GLUCAN SYNTHASE-LIKE 5 (GSL5, also known as POWDERY MILDEW RESISTANT 4), which encodes a callose synthase required for pathogen-induced callose production. Significantly, gsl5 single mutants do not constitutively express PR-1 or AtERF1 (a JA-inducible gene) and are not dwarfed. Thus, loss of both EDR1 and GSL5 function has a synergistic effect. Our data suggest that EDR1 and GSL5 negatively regulate SA and JA production or signaling by independent mechanisms and that negative regulation of defense signaling by GSL5 may be independent of callose production.

scholarly journals Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

1998 ◽  
pp. 96-100 ◽  
Author(s):  
M Peter ◽  
K Bunger ◽  
SL Drop ◽  
WG Sippell
Keyword(s):  
Genetic Study ◽  
Stop Codon ◽  
Molecular Genetic ◽  
Premature Stop Codon ◽  
Type I ◽  
Type Ii ◽  
Loss Of Function ◽  
Molecular Genetic Study ◽  
Base Exchange ◽  
Deficiency Type

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

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