Normal bone mass and normocalcemia in adulthood despite homozygous vitamin D receptor mutations

Damiani, F; Martin, Regina Matsunaga; Latrônico, Ana Claudia; Ferraz-de-Souza, Bruno

doi:10.1007/s00198-015-3076-3

Cited by 13 publications

(7 citation statements)

References 18 publications

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“…As stated earlier, while the male sibling had severe bone loss, the female sibling had normal BMD, an unexpected finding because the female sibling had a more severe form of the disease based on clinical (Genu varum and the need for corrective surgery) and the laboratory findings (low calcium and sky high ALP); the discrepancy can be attributed to the fact that factors other than vitamin D receptors are implicated in bone accretion. Data of the male sibling were very different from those of Tiosano et al and Damiani et al who reported that BMDs of their patients at post-pubertal age were not different from that of the normal population ( 12 , 13 ).…”

Section: Discussioncontrasting

confidence: 79%

Hereditary Vitamin D Resistant Rickets: Clinical, Laboratory, and Genetic Characteristics of 2 Iranian Siblings

Ghazi

Zadeh‐Vakili

Yeganeh

et al. 2017

Int J Endocrinol Metab

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Purpose and MethodsHereditary vitamin D resistant rickets (HVDRR) is a rare disease that presents with signs and symptoms of rickets, alopecia, and growth retardation during the early years of life. The disease is caused by mutations in the vitamin D receptor (VDR) gene, which leads to unresponsiveness of the mutant receptor to 1-25(OH) 2 D3. The disease is transmitted as an autosomal recessive disorder and is found with equal frequency in males and females. The disease is rarely encountered and only about 100 cases are reported so far. The current paper reported the clinical and laboratory characteristics of 2 Iranian siblings with this disorder.Results and ConclusionThey presented with rickets, growth retardation, muscle weakness, hypocalcemia and alopecia totalis since early childhood, and were followed up for 27 years. Sequencing of the DNA extracted from the peripheral white blood cells showed a missense G to A mutation in exon number 4 (g.30994 G > A) that led to the methionine substitution for the naturally occurring valine at position 26 in the DNA binding domain (DBD) of the VDR.

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Section: Discussioncontrasting

confidence: 79%

Hereditary Vitamin D Resistant Rickets: Clinical, Laboratory, and Genetic Characteristics of 2 Iranian Siblings

Ghazi

Zadeh‐Vakili

Yeganeh

et al. 2017

Int J Endocrinol Metab

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“…Indeed, a patient bearing the Gly319Val mutation had a normal bone mass acquisition during young adulthood, but displayed full alopecia. It is intriguing to see the uncoupling of these two processes although normally both would require fully functional VDR (Damiani et al 2015). However, the detailed functional data is not available for this mutation.…”

Section: Ile314ser Vdr Mutantmentioning

confidence: 99%

Structural aspects of Vitamin D endocrinology

Rochel

Molnár

2017

Molecular and Cellular Endocrinology

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1α,25-Dihydroxvitamin D (1,25(OH)D) is the hormonally active form of vitamin D. Its synthesis and its metabolites, their transport and elimination as well as action on transcriptional regulation involves the harmonic cooperation of diverse proteins with vitamin D binding capacities such as vitamin D binding protein (DBP), cytochrome P450 enzymes or the nuclear vitamin receptor (VDR). The genomic mechanism of 1,25(OH)D action involves its binding to VDR that functionally acts as a heterodimer with retinoid X receptor. The crystal structures of the most important proteins for vitamin D, VDR, DBP, CYP2R1 and CYP24A1, have provided identification of mechanisms of actions of these proteins and those mediating VDR-regulated transcription. This review will present the structural information on recognition of the vitamin D and metabolites by CYP proteins and DBP as well as the structural basis of VDR activation by 1,25(OH)D and metabolites. Additionally, we will describe, the implications of the VDR mutants associated with hereditary vitamin D-resistant rickets (HVDRR) that display impaired function.

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“…Some practical tips may help beginners eyeballing several electropherograms: a) updated reference DNA sequences (to be used for comparison) can be obtained from the genome browsers mentioned above; b) considering that genome assemblies and gene annotations may vary from time to time, it is critical to take note and report the identifier of the reference sequence used; and c) be sure to obtain images of critical findings: when reporting Sanger sequencing results, electropherograms displaying the identified variants are customarily shown 25 .…”

Section: Sanger Sequencingmentioning

confidence: 99%

“…Nonsense SNVs are expected to code for truncated proteins with reduced (or abolished) function; therefore, attributing a biological impact is usually more straightforward. For example, we have followed for several decades a patient with severe hereditary vitamin D-resistant rickets due to a nonsense mutation in the vitamin D receptor (VDR) 25 . While wild type VDR has 427 amino acids, this patient's homozygous mutation introduces a premature stop codon at residue 30, meaning that the resulting protein function is severely dysfunctional.…”

Section: Confirming and Ascertaining The Biological Impact Of Dna Varmentioning

confidence: 99%

Diagnóstico molecular na prática clínica: visão do endocrinologista

Ferraz-de-Souza¹

2015

Rev. Med. (São Paulo)

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Endocrinology is one of several medical specialities that have been gradually transformed by a deeper understanding of the molecular bases of disorders. Genetic testing with the purposes of defining a precise molecular diagnosis has increasingly gained space in the routine assessment of patients with endocrinopathies, and the advent of massive parallel sequencing (MPS) is boosting the incorporation of molecular information in the clinic. The main benefit of genetic testing is diagnostic precision, resulting in improved and individualized care for patients and family members, and better disease prevention. However, genetic tests are not infallible and may bear several potential risks, being thus indicated when clinical suspicion is strong and the benefit of determining a molecular diagnosis is unambiguous. In this review, these evolving concepts and current indications for molecular diagnosis in endocrinology will be explored. Molecular tools will be revised and contextualised, including those aimed at identifying changes in gene dosage (karyotpe, FISH, MLPA, aCGH, SNParray) or in the DNA nucleotide sequence (allele-specific PCR, RFLP, Sanger sequencing, MPS or NGS). Finally, matters surrounding the complex attribution of biologically relevant functional impact to identified DNA variants will be explored, together with the challenges brought by high throughput molecular analysis. These are exciting times for molecular endocrinology, and hopefully soon a translation to multiple benefits for patients will be self-evident.Keywords: Genetic testing; Endocrinology; Mutation; DNA mutation analysis; Transcription, genetic; Genetic markers; Sequence analysis, DNA/methdos; Molecular sequence data. RESUMO:A endocrinologia é uma de muitas especialidades médicas que vem sendo transformada pelo maior conhecimento das bases moleculares das doenças. O teste genético com o propósito de definir o diagnóstico molecular vem ganhando espaço na avaliação rotineira de pacientes com endocrinopatias, e o advento do sequenciamento paralelelo em larga escala (SPLE) está ampliando o potencial de incorporação da informação molecular na prática clínica. O principal benefício do teste genético é a precisão diagnóstica, resultando em melhora e individualização do tratamento de pacientes e seus familiares, e da prevenção de doenças. Entretanto, testes genéticos não são infalíveis e podem trazer alguns riscos potenciais, estando portanto indicados quando a suspeita clínica é forte e o benefício do diagnóstico molecular é claro. Nesta revisão serão explorados conceitos genéticos em evolução e as atuais indicações de diagnóstico molecular em endocrinologia. Ferramentas moleculares serão revisadas, incluindo aquelas visando a identificação de alterações no número de cópias gênicas (cariótipo, FISH, MLPA, aCGH, SNParray) ou na sequencia nucleotídica do DNA (PCR alelo-específica, RFLP, sequenciamento Sanger, SPLE ou NGS). Ainda, serão discutidos os percalços da difícil atribuição de impacto funcional e relevância biológica a variantes de DN...

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Normal bone mass and normocalcemia in adulthood despite homozygous vitamin D receptor mutations

Cited by 13 publications

References 18 publications

Hereditary Vitamin D Resistant Rickets: Clinical, Laboratory, and Genetic Characteristics of 2 Iranian Siblings

Hereditary Vitamin D Resistant Rickets: Clinical, Laboratory, and Genetic Characteristics of 2 Iranian Siblings

Structural aspects of Vitamin D endocrinology

Diagnóstico molecular na prática clínica: visão do endocrinologista

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