Analysis of pathogenic variants in a Chinese pedigree affected with hyaline fibromatosis syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic basis for a pair of twins affected with hyaline fibromatosis syndrome (HFS).@*METHODS@#Clinical data of the twins were retrospectively analyzed. High-throughput sequencing was carried out to detect potential pathogenic variants. CLUSTALX was employed to analyze cross-species conservation of the mutant amino acids. Impact of the mutations was predicted by using software including PolyPhen-2 and Mutation taster.@*RESULTS@#The pair of twins have featured growth and intelligence retardation, and were found to carry compound heterozygous variants of the ANTXR2 gene including c.1214G>A and c.1074delT, among which c.1214G>A was unreported previously. Both variants were predicted to be pathogenic. In addition to growth and mental delay, the pair of twins also featured hyperplasia of the gum and soft tissue-like masses of the auricle. The younger brother had rupture of the auricle mass during follow-up.@*CONCLUSION@#The patients' condition can probably be attributed to the compound heterozygous variants of the ANTXR2 gene. Above finding has facilitated molecular diagnosis of the patients.

Relaxin Receptor RXFP1 and RXFP2 Expression in Ligament, Tendon, and Shoulder Joint Capsule of Rats

Numerous musculoskeletal disorders are caused by thickened ligament, tendon stiffness, or fibrosis of joint capsule. Relaxin, a peptide hormone, can exert collagenolytic effect on ligamentous and fibrotic tissues. We hypothesized that local injection of relaxin could be used to treat entrapment neuropathy and adhesive capsulitis. Because hormonal effect depends on the receptor of the hormone on the target cell, it is important to confirm the presence of such hormonal receptor at the target tissue before the hormone therapy is initiated. The aim of this study was to determine whether there were relaxin receptors in the ligament, tendon, and joint capsular tissues of rats and to identify the distribution of relaxin receptors in these tissues. Transverse carpal ligaments (TCLs), inguinal ligaments, anterior cruciate ligaments (ACLs), Achilles tendons, and shoulder joint capsules were obtained from male Wistar rats. Western blot analysis was used to identify relaxin receptor isoforms RXFP1 and RXFP2. The distribution of relaxin receptors was determined by immunohistochemical staining. The RXFP1 isoform was found in all tissues examined. The RXFP2 isoform was present in all tissues but the TCLs. Its expression in ACLs tissues was relatively weak compared to that in other tissues. Our results revealed that RXFP1 and RXFP2 were distributed in distinctly different patterns according to the type of tissue (vascular endothelial cells, fibroblast-like cells) they were identified.

Analysis of anti-Müllerian hormone (AMH) and its receptor (AMHR2) genes in patients with persistent Müllerian duct syndrome / Pesquisa de mutações nos genes do hormônio antiMülleriano (AMH) e do seu receptor (AMHR2) em pacientes com síndrome de persistência dos ductos Müllerianos

OBJECTIVE: To screen for mutations in AMH and AMHR2 genes in patients with persistent Müllerian duct syndrome (PMDS). PATIENTS AND METHOD: Genomic DNA of eight patients with PMDS was obtained from peripheral blood leukocytes. Directed sequencing of the coding regions and the exon-intron boundaries of AMH and AMHR2 were performed. RESULTS: The AMH mutations p.Arg95*, p.Arg123Trp, c.556-2A>G, and p.Arg502Leu were identified in five patients; and p.Gly323Ser and p.Arg407* in AMHR2 of two individuals. In silico analyses of the novel c.556-2A>G, p.Arg502Leu and p.Arg407* mutations predicted that they were harmful and were possible causes of the disease. CONCLUSION: A likely molecular etiology was found in the eight evaluated patients with PMDS. Four mutations in AMH and two in AMHR2 were identified. Three of them are novel mutations, c.556-2A>G, and p.Arg502Leu in AMH; and p.Gly323Ser in AMHR2. Arq Bras Endocrinol Metab. 2012;56(8):473-8.

OBJETIVO: Analisar os genes AMH e AMHR2 em indivíduos com síndrome de persistência dos ductos de Müller (SPDM). PACIENTES E MÉTODO: Amostras de DNA genômico de oito pacientes com SPDM foram obtidas de leucócitos de sangue periférico. Sequenciamento direto da região codificadora e das áreas intrônicas próximas aos éxons dos genes AMH e AMHR foi realizado. RESULTADOS: As mutações p.Arg95*, p.Arg123Trp, c.556-2A>G e p.Arg502Leu no gene AMH foram identificadas em cinco pacientes e as mutações p.Gly323Ser e p.Arg407* no gene AMHR2, em dois indivíduos. As análises in silico das mutações c.556-2A>G, p.Arg502Leu e p.Arg407*, não descritas anteriormente na literatura, previram que elas são deletérias e possivelmente a causa da doença. CONCLUSÃO: Uma provável etiologia molecular foi encontrada nos oito pacientes portadores de SPDM avaliados. No gene do AMH foram identificadas quatro mutações e no AMHR2, duas mutações. Três das seis mutações encontradas são mutações novas, c.556-2A>G e p.Arg502Leu no gene AMH; e p.Gly323Ser no AMHR2. Arq Bras Endocrinol Metab. 2012;56(8):473-8.

Síndrome de Kallmann: uma revisão histórica, clínica e molecular / Kallmann syndrome: a hystorical, clinical and molecular review

A síndrome de Kallmann (SK) é a associação de hipogonadismo hipogonadotrófico (HH) e anosmia descrita por Maestre de San Juan, em 1856, e caracterizada como condição hereditária por Franz Josef Kallmann, em 1944. Muitos aspectos de sua patogenia, variabilidade fenotípica e genotípica foram desvendados nos últimos 15 anos. Conseqüentemente, tem sido difícil manter-se atualizado frente à rapidez que o conhecimento dessa condição é gerado. Nesta revisão, resgatamos aspectos históricos pouco conhecidos sobre a síndrome e seus descobridores; incorporamos novas descobertas relacionadas à embriogênese dos neurônios olfatórios e produtores de GnRH. Esse processo é fundamental para compreender a associação de hipogonadismo e anosmia; descrevemos a heterogeneidade fenotípica e genotípica, incluindo mutações em cinco genes (KAL-1, FGFR1, PROKR2, PROK2 e NELF). Para cada gene, discutimos a função da proteína codificada na migração e maturação dos neurônios olfatórios e GnRH a partir de estudos in vitro e modelos experimentais e descrevemos características clínicas dos portadores dessas mutações.

Kallmann syndrome (KS), the association of hypogonadotropic hypogonadism and anosmia, was described by Maestre de San Juan in 1856 and characterized as a hereditary condition by Franz Josef Kallmann in 1944. Many aspects such as pathogeny, phenotype and genotype in KS were described in the last fifteen years. The knowledge of this condition has grown fast, making it difficult to update. Here we review historical aspects of this condition and its discoverers and describe new findings regarding the embryogenesis of the olfactory bulb and GnRH secreting neuronal tracts that are important for understanding the association of hypogonadism and anosmia. Additionally, we describe the phenotypic and genotypic heterogeneity of KS, including five related genes (KAL-1, FGFR1, PROKR2, PROK2 e NELF), and discuss the function of each codified protein in migration and maturation of the olfactory and GnRH neurons, with data from in vitro and in vivo studies. Finally we describe the clinical phenotype of patients carrying these mutations.