RESUMEN
BACKGROUND: Osteopetrosis is a group of geneticall heterogeneous disorders resulting from impaired osteoclast function and bone resorption. The identification of specific genetic mutations can yield important prognostic and therapeutic implications. Herein, we present the diagnosis and successful application of hematopoietic stem cell transplantation (HSCT) in a patient with osteopetrosis caused by carbonic anhydrase II deficiency (Intermediate osteopetrosis). CASE PRESENTATION: Herein, we describe a 2.5-year-old male patient born to consanguineous parents who presented at 8-month-old with hydrocephaly, brain shunt, and developmental delay. Later at 9 months old, he was found to have eye disorder such as nystagmus, fracture of the elbow, abnormal skeletal survey, normal cell blood count (CBC), and severe hypocellularity in the bone marrow. Further evaluation showed renal tubular acidosis type 2. Whole-exome sequencing revealed a pathogenic homozygous variant in intron 2 of the carbonic anhydrase 2 gene (CA2) gene (c.232 + 1 G>T). The diagnosis of intermediate autosomal recessive osteopetrosis was established, and allogenic HSCT from his mother, a full-matched related donor (MRD), was planned. The conditioning regimen included Busulfan, Fludarabine, and Rabbit anti-thymocyte globulin. Cyclosporine and Mycophenolate Mofetil were used for graft-versus-host-disease prophylaxis. He Engrafted on day +13, and 95% chimerism was achieved. He is currently doing well without immunosuppressive therapy, now 12 months post HSCT, with normal calcium level and improving visual quality and FISH analysis revealed complete donor chimerism. DISCUSSION: HSCT could be a promising curative treatment for intermediate osteopetrosis and can provide long-term survival. Ongoing challenges in various aspects of HSCT remain to be addressed.
Asunto(s)
Anhidrasas Carbónicas/deficiencia , Trasplante de Células Madre Hematopoyéticas , Osteopetrosis , Trastornos Innatos del Ciclo de la Urea , Humanos , Masculino , Osteopetrosis/genética , Osteopetrosis/terapia , Preescolar , Irán , Anhidrasa Carbónica II/genética , Anhidrasa Carbónica II/deficiencia , Acidosis Tubular Renal/genética , Acidosis Tubular Renal/terapia , Trasplante HomólogoRESUMEN
Carbonic anhydrase II deficiency (OMIM # 259730), initially called "osteopetrosis with renal tubular acidosis and cerebral calcification syndrome", reveals an important role for the enzyme carbonic anhydrase II (CA II) in osteoclast and renal tubule function. Discovered in 1972 and subsequently given various names, CA II deficiency now describes >100 affected individuals encountered predominantly from the Middle East and Mediterranean region. In 1983, CA II deficiency emerged as the first osteopetrosis (OPT) understood metabolically, and in 1991 the first understood molecularly. CA II deficiency is the paradigm OPT featuring failure of osteoclasts to resorb bone due to inability to acidify their pericellular milieu. The disorder presents late in infancy or early in childhood with fracturing, developmental delay, weakness, short stature, and/or cranial nerve compression and palsy. Mental retardation is common. The skeletal findings may improve by adult life, and CA II deficiency can be associated with a normal life-span. Therefore, it has been considered an "intermediate" type of OPT. In CA II deficiency, OPT is uniquely accompanied by renal tubular acidosis (RTA) of proximal, distal, or combined type featuring hyperchloremic metabolic acidosis, rarely with hypokalemia and paralysis. Cerebral calcification uniquely appears in early childhood. The etiology is bi-allelic loss-of-function mutations of CA2 that encodes CA II. Prenatal diagnosis requires mutational analysis of CA2. Although this enzymopathy reveals how CA II is important for the skeleton and kidney tubule, the pathogenesis of the mental subnormality and cerebral calcification is less well understood. Several mouse models of CA II deficiency have shown growth hormone deficiency, yet currently there is no standard pharmacologic therapy for patients. Treatment of the systemic acidosis is often begun when growth is complete. Although CA II deficiency is an "osteoclast-rich" OPT, and therefore transplantation of healthy osteoclasts can improve the skeletal disease, the RTA and central nervous system difficulties persist.
Asunto(s)
Acidosis Tubular Renal , Calcinosis , Anhidrasa Carbónica II , Anhidrasas Carbónicas , Discapacidad Intelectual , Osteopetrosis , Trastornos Innatos del Ciclo de la Urea , Animales , Preescolar , Femenino , Humanos , Ratones , Embarazo , Acidosis Tubular Renal/complicaciones , Acidosis Tubular Renal/genética , Calcinosis/genética , Anhidrasas Carbónicas/genética , Discapacidad Intelectual/genética , Osteopetrosis/genética , Trastornos Innatos del Ciclo de la Urea/complicaciones , Anhidrasa Carbónica II/deficienciaRESUMEN
BACKGROUND: Carbonic anhydrase II deficiency syndrome is an autosomal recessive osteopetrosis with renal tubular acidosis and cerebral calcifications. We tried to detect the causative mutation for carbonic anhydrase II deficiency syndrome in a five-generation Chinese family. MATERIALS AND METHODS: Genomic DNA was extracted from whole blood of the proband, his grandmother, parents, aunt, uncle and sister. The exomes were sequenced by whole exon sequencing followed by genetic analysis and Sanger sequencing validation. Then, physical and chemical properties studies and structure analysis were performed on mutated protein. Finally, Minigene model of vector plasmids for wild type and mutant type was constructed and transfected into human embryonic kidney 293T cells to further explore the expression change of CA2 transcript and protein after mutation. RESULTS: Sequencing and genetic analysis have revealed the homozygous nonsense mutation of CA2 gene (c.368G > A, p.W123X) in the exon 4 of chromosome 8 of the proband, while it was not found in his grandmother, parents, aunt, uncle and sister. Furthermore, Sanger sequencing in the proband and his parents validated the mutation. Properties and structure of mutated CA2 proteins changed after mutation, especially in change of protein modification and hindrance of zinc ions binding, which may lead to decreased protein expression level of CA2. CONCLUSIONS: We found a new homozygous nonsense mutation in CA2 gene (c.368G > A, p.W123X), which may be valuable in the early diagnosis and therapy of carbonic anhydrase II deficiency syndrome.
Asunto(s)
Pueblo Asiatico/genética , Anhidrasa Carbónica II/deficiencia , Anhidrasa Carbónica II/genética , Codón sin Sentido/genética , Homocigoto , Anhidrasa Carbónica II/química , Células HEK293 , Humanos , Masculino , Linaje , Estructura Secundaria de Proteína , Adulto JovenRESUMEN
Carbonic anhydrase II knockout (Car2-/-) mice have depleted numbers of renal intercalated cells, which are increasingly recognized to be innate immune effectors. We compared pyelonephritis susceptibility following reciprocal renal transplantations between Car2-/- and wild-type mice. We examined the effect of pharmacological CA suppression using acetazolamide in an experimental murine model of urinary tract infection. Car2-/- versus wild-type mice were compared for differences in renal innate immunity. In our transplant scheme, mice lacking CA-II in the kidney had increased pyelonephritis risk. Mice treated with acetazolamide had lower kidney bacterial burdens at 6 h postinfection, which appeared to be due to tubular flow from diuresis because comparable results were obtained when furosemide was substituted for acetazolamide. Isolated Car2-/- kidney cells enriched for intercalated cells demonstrated altered intercalated cell innate immune gene expression, notably increased calgizzarin and insulin receptor expression. Intercalated cell number and function along with renal tubular flow are determinants of pyelonephritis risk.
Asunto(s)
Acetazolamida/farmacología , Anhidrasa Carbónica II/deficiencia , Inhibidores de Anhidrasa Carbónica/farmacología , Infecciones por Escherichia coli/prevención & control , Riñón/efectos de los fármacos , Pielonefritis/prevención & control , Infecciones Urinarias/prevención & control , Acidosis/enzimología , Acidosis/genética , Animales , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/genética , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/enzimología , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/microbiología , Regulación del Desarrollo de la Expresión Génica , Predisposición Genética a la Enfermedad , Inmunidad Innata , Riñón/enzimología , Riñón/inmunología , Riñón/microbiología , Trasplante de Riñón , Ratones Endogámicos C57BL , Ratones Noqueados , Pielonefritis/enzimología , Pielonefritis/genética , Pielonefritis/microbiología , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Infecciones Urinarias/enzimología , Infecciones Urinarias/genética , Infecciones Urinarias/microbiología , Escherichia coli Uropatógena/patogenicidadRESUMEN
Improving acid tolerance is pivotal to the development of microalgal feedstock for converting flue gas to biomass or oils. In the industrial oleaginous microalga Nannochloropsis oceanica, transcript knockdown of a cytosolic carbonic anhydrase (CA2), which is a key Carbon Concentrating Mechanism (CCM) component induced under 100â¯ppm CO2 (very low carbon, or VLC), results in â¼45%, â¼30% and â¼40% elevation of photosynthetic oxygen evolution rate, growth rate and biomass accumulation rate respectively under 5% CO2 (high carbon, or HC), as compared to the wild type. Such high-CO2-level activated biomass over-production is reproducible across photobioreactor types and cultivation scales. Transcriptomic, proteomic and physiological changes of the mutant under high CO2 (HC; 5% CO2) suggest a mechanism where the higher pH tolerance is coupled to reduced biophysical CCM, sustained pH hemostasis, stimulated energy intake and enhanced photosynthesis. Thus "inactivation of CCM" can generate hyper-CO2-assimilating and autonomously containable industrial microalgae for flue gas-based oil production.
Asunto(s)
Dióxido de Carbono/metabolismo , Anhidrasa Carbónica II/deficiencia , Técnicas de Silenciamiento del Gen , Microalgas/metabolismo , Fotosíntesis , Estramenopilos/metabolismo , Concentración de Iones de Hidrógeno , Microalgas/genética , Estramenopilos/genéticaRESUMEN
Rapid exchange of metabolites between different cell types is crucial for energy homeostasis of the brain. Besides glucose, lactate is a major metabolite in the brain and is primarily produced in astrocytes. In the present study, we report that carbonic anhydrase 2 (CAII) enhances both influx and efflux of lactate in mouse cerebellar astrocytes. The augmentation of lactate transport is independent of the enzyme's catalytic activity, but requires direct binding of CAII to the C-terminal of the monocarboxylate transporter MCT1, one of the major lactate/proton cotransporters in astrocytes and most tissues. By employing its intramolecular proton shuttle, CAII, bound to MCT1, can act as a 'proton collecting antenna' for the transporter, suppressing the formation of proton microdomains at the transporter-pore and thereby enhancing lactate flux. By this mechanism CAII could enhance transfer of lactate between astrocytes and neurons and thus provide the neurons with an increased supply of energy substrate.
Asunto(s)
Astrocitos/metabolismo , Anhidrasa Carbónica II/metabolismo , Cerebelo/metabolismo , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Animales , Anhidrasa Carbónica II/deficiencia , Anhidrasa Carbónica II/genética , Células Cultivadas , Femenino , Ratones , Ratones Noqueados , Transportadores de Ácidos Monocarboxílicos/genética , Oocitos , ARN Interferente Pequeño/genética , Simportadores/genética , Xenopus laevisRESUMEN
Carbonic anhydrase type II deficiency syndrome is an uncommon autosomal recessive disease with cardinal features including osteopetrosis, renal tubular acidosis and brain calcifications. We describe the neurological, neuro-ophthalmological and neuroradiological features of 23 individuals (10 males, 13 females; ages at final examination 2-29 years) from 10 unrelated consanguineous families with carbonic anhydrase type II deficiency syndrome due to homozygous intron 2 splice site mutation (the 'Arabic mutation'). All patients had osteopetrosis, renal tubular acidosis, developmental delay, short stature and craniofacial disproportion with large cranial vault and broad forehead. Mental retardation was present in approximately two-thirds and varied from mild to severe. General neurological examinations were unremarkable except for one patient with brisk deep tendon reflexes and two with severe mental retardation and spastic quadriparesis. Globes and retinae were normal, but optic nerve involvement was present in 23/46 eyes and was variable in severity, random in occurrence and statistically correlated with degree of optic canal narrowing. Ocular motility was full except for partial ductional limitations in two individuals. Saccadic abnormalities were present in two, while half of these patients had sensory or accommodative strabismus, and seven had congenital nystagmus. These abnormalities were most commonly associated with afferent disturbances, but a minor brainstem component to this disorder remains possible. All internal auditory canals were normal in size, and no patient had clinically significant hearing loss. Neuroimaging was performed in 18 patients and repeated over as long as 10 years. Brain calcification was generally progressive and followed a distinct distribution, involving predominantly basal ganglia and thalami and grey-white matter junction in frontal regions more than posterior regions. At least one child had no brain calcification at age 9 years, indicating that brain calcification may not always be present in carbonic anhydrase type II deficiency syndrome during childhood. Variability of brain calcification, cognitive disturbance and optic nerve involvement may imply additional genetic or epigenetic influences affecting the course of the disease. However, the overall phenotype of the disorder in this group of patients was somewhat less severe than reported previously, raising the possibility that early treatment of systemic acidosis with bicarbonate may be crucial in the outcome of this uncommon autosomal recessive problem.
Asunto(s)
Acidosis Tubular Renal/fisiopatología , Encéfalo/fisiopatología , Anhidrasa Carbónica II/deficiencia , Anomalías Craneofaciales/fisiopatología , Discapacidad Intelectual/fisiopatología , Osteopetrosis/fisiopatología , Acidosis Tubular Renal/genética , Adolescente , Adulto , Calcinosis/genética , Calcinosis/fisiopatología , Anhidrasa Carbónica II/genética , Niño , Preescolar , Anomalías Craneofaciales/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Neuroimagen , Osteopetrosis/genética , Linaje , SíndromeRESUMEN
Carbonic anhydrase II (CAII) deficiency syndrome characterized by osteopetrosis (OP), renal tubular acidosis (RTA), and cerebral calcifications is caused by mutations in the carbonic anhydrase 2 (CA2) gene. Severity of this disorder varies depending on the nature of the mutation and its effect on the protein. We present here, the clinical and radiographic details along with, results of mutational analysis of the CA2 gene in an individual clinically diagnosed with renal tubular acidosis, osteopetrosis and mental retardation and his family members to establish genotype-phenotype correlation. A novel homozygous deletion mutation c.251delT was seen in the patient resulting in a frameshift and a premature stop codon at amino acid position 90 generating a truncated protein leading to a complete loss of function and a consequential deficiency of the enzyme making this a pathogenic mutation. Confirmation of clinical diagnosis by molecular methods is essential as the clinical features of the CAII deficiency syndrome are similar to other forms of OP but the treatment modalities are different. Genetic confirmation of the diagnosis at an early age leads to the timely institution of therapy improving the growth potential, reduces other complications like fractures, and aids in providing prenatal testing and genetic counseling to the parents planning a pregnancy.
Asunto(s)
Acidosis Tubular Renal/genética , Anhidrasa Carbónica II/deficiencia , Anhidrasa Carbónica II/genética , Mutación del Sistema de Lectura/genética , Discapacidad Intelectual/genética , Osteopetrosis/genética , Acidosis Tubular Renal/diagnóstico , Acidosis Tubular Renal/enzimología , Adulto , Calcinosis/diagnóstico , Calcinosis/enzimología , Calcinosis/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/enzimología , Masculino , Osteopetrosis/diagnóstico , Osteopetrosis/enzimología , Linaje , Fenotipo , Análisis de Secuencia de ADN , SíndromeRESUMEN
Osteopetrosis is the result of mutations affecting osteoclast function. Careful analyses of osteopetrosis have provided instrumental information on bone remodeling, including the coupling of bone formation to bone resorption. Based on a range of novel genetic mutations and the resulting osteoclast phenotypes, we discuss how osteopetrosis models have clarified the function of the coupling of bone formation to bone resorption, and the pivotal role of the osteoclast and their function in this phenomenon. We highlight the distinct possibility that osteoclast activities can be divided into two separate avenues: bone resorption and control of bone formation.
Asunto(s)
Mutación , Osteoclastos/fisiología , Osteopetrosis/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas Relacionadas con la Autofagia , Remodelación Ósea/genética , Remodelación Ósea/fisiología , Resorción Ósea/genética , Resorción Ósea/fisiopatología , Anhidrasa Carbónica II/deficiencia , Anhidrasa Carbónica II/genética , Catepsina K , Catepsinas/genética , Canales de Cloruro/genética , Modelos Animales de Enfermedad , Humanos , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Ratones , Modelos Biológicos , Osteoblastos/patología , Osteoblastos/fisiología , Osteoclastos/patología , Osteopetrosis/etiología , Osteopetrosis/patología , Osteopetrosis/fisiopatología , Ligando RANK/deficiencia , Ligando RANK/genética , Receptor Activador del Factor Nuclear kappa-B/deficiencia , Receptor Activador del Factor Nuclear kappa-B/genética , Ubiquitina-Proteína Ligasas/genética , ATPasas de Translocación de Protón Vacuolares/genéticaRESUMEN
Lack of or dysfunction in osteoclasts result in osteopetrosis, a group of rare but often severe, genetic disorders affecting skeletal tissue. Increase in bone mass results in skeletal malformation and bone marrow failure that may be fatal. Many of the underlying defects have lately been characterized in humans and in animal models of the disease. In humans, these defects often involve mutations in genes expressing proteins involved in the acidification of the osteoclast resorption compartment, a process necessary for proper bone degradation. So far, the only cure for children with severe osteopetrosis is allogeneic hematopoietic stem cell (HSC) transplantation but without a matching donor this form of therapy is far from optimal. The characterization of the genetic defects opens up the possibility for gene replacement therapy as an alternative. Accordingly, HSC-targeted gene therapy in a mouse model of infantile malignant osteopetrosis was recently shown to correct many aspects of the disease.
Asunto(s)
Osteopetrosis/etiología , Osteopetrosis/terapia , Animales , Anhidrasa Carbónica II/deficiencia , Canales de Cloruro/deficiencia , Terapia Genética/métodos , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Recién Nacido , Ratones , Mutación , Osteoclastos/fisiología , Osteopetrosis/fisiopatología , Bombas de Protones/deficienciaRESUMEN
BACKGROUND/AIMS: Intercalated cells (ICs) of the kidney collecting duct are rich in carbonic anhydrase II (CAII), which facilitates proton and bicarbonate transport. Bicarbonate secretion is mediated via Pendrin (Slc26a4), which is expressed on the apical membrane of B-ICs and nonA-nonB ICs in the cortical collecting ducts (CCD). Bicarbonate absorption is mediated via anion exchanger 1 (AE1-Slc4a1) in the CCD and via AE1 and possibly Slc26a7 in the OMCD. Both exchangers are expressed on the basolateral membrane of A-ICs. The aim of this study was to examine the expression of pendrin, Slc26a7, and AE1 in the kidneys of CAII-deficient (CAR2-null) mice. METHODS: For the expression studies, we used real-time RT-PCR, Northern hybridization, immunolabeling, and immunoblotting. RESULTS: Pendrin mRNA expression was reduced 63% along with decreased pendrin immunolabeling in the cortex of CAR2-null mice present predominantly in nonA-nonB ICs. Slc26a7 mRNA expression was decreases by 73% and Slc26a7 immunolabeling, present in A-ICs, severely reduced in the outer medulla of CAR2-null mice. AE1 mRNA expression was decreased to a similar degree (62%) along with reduced AE1 immunolabeling. The expression of aquaporin 2 (AQP2) water channel, exclusively present in principal cells of the collecting duct, was comparable in the wild type and CAR2-null mice. CONCLUSION: CAII deficiency results in a significant decrease in the gene and protein expression of bicarbonate transport proteins from Slc26 gene family - Slc26a4 (pendrin) and Slc26a7. These results emphasize the critical role of CAII for the maintenance of the intercalated cell phenotype.
Asunto(s)
Proteínas de Transporte de Anión/genética , Proteínas de Transporte de Anión/metabolismo , Anhidrasa Carbónica II/deficiencia , Antiportadores de Cloruro-Bicarbonato/genética , Antiportadores de Cloruro-Bicarbonato/metabolismo , Riñón/enzimología , Animales , Proteína 1 de Intercambio de Anión de Eritrocito/genética , Proteína 1 de Intercambio de Anión de Eritrocito/metabolismo , Acuaporina 2/genética , Acuaporina 2/metabolismo , Western Blotting , Densitometría , Regulación de la Expresión Génica , Riñón/citología , Ratones , ATPasas de Translocación de Protón/metabolismo , Transportadores de SulfatoAsunto(s)
Osteopetrosis , Animales , Trasplante de Médula Ósea , Resorción Ósea/genética , Calcitriol/administración & dosificación , Anhidrasa Carbónica II/deficiencia , Canales de Cloruro/genética , Diagnóstico Diferencial , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad , Osteoclastos/fisiología , Osteopetrosis/clasificación , Osteopetrosis/diagnóstico , Osteopetrosis/etiología , Osteopetrosis/terapia , Pronóstico , ATPasas de Translocación de Protón Vacuolares/genéticaAsunto(s)
Anhidrasa Carbónica II/deficiencia , Síndrome de Fanconi , Acidosis Tubular Renal/etiología , Álcalis/uso terapéutico , Bicarbonatos/metabolismo , Trasplante de Médula Ósea , Anhidrasa Carbónica II/genética , Anhidrasa Carbónica II/fisiología , Síndrome de Fanconi/etiología , Síndrome de Fanconi/fisiopatología , Humanos , Túbulos Renales Distales/metabolismo , Túbulos Renales Proximales/metabolismo , Osteopetrosis/etiologíaRESUMEN
Carbonic anhydrase II (CA-II)-deficient mice have long circadian periods compared to their siblings with normal CA-II levels. The CA-II-deficient mice differ genetically from their siblings at proximal chromosome three, where the mutated carbonic anhydrase 2 gene sits on a small insert of DNA from the DBA/2J strain. The rest of the genome is that of the C57BL/6J strain. The goal of this study was to test the hypothesis that the null mutation in carbonic anhydrase 2 and the long circadian period phenotype were linked. In order to separate the effect of the null mutation in carbonic anhydrase 2 from the effect of DBA/2J alleles of other genes on the insert, two new lines of mice were studied. The first line, Kar, was developed from a CA-II-deficient mouse that had a fortuitous recombination restoring functional CA-II without affecting the rest of the DBA/2J insert. The second line was generated by breeding DBA/2J mice and C57BL/6J mice until they had the genomic composition of CA-II-deficient mice without the null mutation. Both lines of mice had circadian periods not different from C57BL/6J mice and shorter than CA-II-deficient mice. The phenotype of the new lines showed that the long circadian period characteristic of the CA-II-deficient mice arises when functional CA-II is absent, not when DBA/2J alleles are present on proximal chromosome three.
Asunto(s)
Anhidrasa Carbónica II/deficiencia , Anhidrasa Carbónica II/genética , Ritmo Circadiano/genética , Alelos , Animales , Secuencia de Bases/genética , Cromosomas de los Mamíferos/genética , Exones/genética , Heterocigoto , Homocigoto , Intrones/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Modelos Genéticos , Mutagénesis Insercional , Fenotipo , Recombinación Genética/genéticaRESUMEN
Carbonic anhydrase II (CA2) deficiency syndrome is an autosomal recessive disorder leading to osteopetrosis, renal tubular acidosis, and cerebral calcifications. Affected members of an Arab family with the CA2 deficiency syndrome carried the "Egyptian mutation" in CA2, i.e., c.191 del A, H64fsX90. One affected member, homozygote for the mutation, developed primary pulmonary hypertension. Primary pulmonary hypertension was never described before in patients with this unique syndrome. The likelihood of both occurring randomly in a single individual is very low. We therefore speculate that there might be a possibility of an etiologic link between these entities.
Asunto(s)
Acidosis Tubular Renal/diagnóstico , Encefalopatías/diagnóstico , Calcinosis/diagnóstico , Anhidrasa Carbónica II/deficiencia , Osteopetrosis/diagnóstico , Acidosis Tubular Renal/enzimología , Acidosis Tubular Renal/genética , Encefalopatías/enzimología , Encefalopatías/genética , Calcinosis/enzimología , Calcinosis/genética , Anhidrasa Carbónica II/genética , Preescolar , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/genética , Lactante , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/genética , Masculino , Mutación , Osteopetrosis/enzimología , Osteopetrosis/genética , SíndromeAsunto(s)
Acidosis Tubular Renal/etiología , Anhidrasa Carbónica II/deficiencia , Absorciometría de Fotón , Acidosis Tubular Renal/tratamiento farmacológico , Acidosis Tubular Renal/enzimología , Adolescente , Bicarbonatos/uso terapéutico , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Calcio/orina , Anhidrasa Carbónica II/genética , Núcleo Caudado/diagnóstico por imagen , Núcleo Caudado/patología , Consanguinidad , Análisis Mutacional de ADN , Femenino , Fracturas Espontáneas/diagnóstico por imagen , Fracturas Espontáneas/etiología , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/patología , Huesos del Metacarpo/diagnóstico por imagen , Huesos del Metacarpo/patología , Nefrocalcinosis/enzimología , Nefrocalcinosis/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Neuroglía/enzimología , Osteoblastos/fisiología , Osteoclastos/fisiología , Osteopetrosis/complicaciones , Osteopetrosis/diagnóstico por imagen , Osteopetrosis/enzimología , Osteopetrosis/genética , Osteopetrosis/patología , Mutación Puntual , Tomografía Computarizada por Rayos XRESUMEN
Twenty four patients suffering from osteopetrosis caused by carbonic anhydrase II deficiency are colliged. This pathology seems to be frequent in Tunisia. Mental retardation is present in 52%, 85% of patients have short stature and 25% have optic atrophy. All affected subjects show craniofacial disproportion and dental anomalies. Twenty patients have at least one bone fracture. Metabolic acidosis is constant: it is profound during the first life decade. A severe selective reduction of carbonic anhydrase II in erythrocyte is confirmed in 18 cases. Osteosclerosis and defective skeletal modelling are constant, cerebral calcification can be seen at the scanner approximately at the age of two years and six months. All patients are homozygous for a splice junction mutation in intron 2 of the carbonic anhydrase II gene, this mutation does not seem to protect patients from bone fractures nor induce a severe metabolic acidosis.
Asunto(s)
Anhidrasa Carbónica II/deficiencia , Osteopetrosis/etiología , Adolescente , Anhidrasa Carbónica II/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Intrones , Masculino , Mutación , Osteopetrosis/genética , TúnezRESUMEN
The authors present a case of osteopetrosis due to carbonic anhydrase II deficiency. Clinical, laboratory and radiologic findings are reported. The genetics of osteopetrosis are reviewed.
Asunto(s)
Acidosis Tubular Renal/etiología , Encéfalo/patología , Anhidrasa Carbónica II/deficiencia , Osteopetrosis/etiología , Acidosis Tubular Renal/genética , Calcinosis , Humanos , Lactante , Masculino , Osteopetrosis/genéticaRESUMEN
The carbonic anhydrase II (CA II) deficiency syndrome is an autosomal recessive disorder that produces osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include developmental delay, short stature, cognitive defects, and a history of multiple fractures by adolescence. With one exception, all patients with osteopetrosis and renal tubular acidosis examined have proven to have CA II deficiency. All CA II-deficient patients analyzed have been found to have mutations in the CA2 gene. Previously, we used single strand conformational (SSCP) analysis to identify exons to be sequenced from CA II-deficient patients. In this report, we amplified all seven exons by PCR from genomic DNA and directly sequenced the amplified products. Application of this method allowed identification of eleven new mutations in 21 patients referred for confirmation of the diagnosis of CA II deficiency. These mutations were scattered over the genome from exon 2 to 7. In two opportunities for prenatal diagnosis, one from cultured amniocytes and one from chorionic villus biopsy, we demonstrated the general utility of the direct sequencing method for prenatal DNA diagnosis. These studies expand our knowledge of the heterogeneity in mutations underlying the CA II deficiency syndrome.