The DUX4 protein is a co-repressor of the progesterone and glucocorticoid nuclear receptors.

DUX4 is a transcription factor required during early embryonic development in placental mammals. In this work, we provide evidence that DUX4 is a co-repressor of nuclear receptors (NRs) of progesterone (PR) and glucocorticoids (GR). The DUX4 C-ter and N-ter regions, including the nuclear localization signals and homeodomain motifs, contribute to the co-repressor activity of DUX4 on PR and GR. Immunoprecipitation studies, using total protein extracts of cells expressing tagged versions of DUX4 and GR, support that these proteins are physically associated. Our studies suggest that DUX4 could modulate gene expression by co-regulating the activity of hormone NRs. This is the first report highlighting a potential endocrine role for DUX4.

A complex interplay of genetic and epigenetic events leads to abnormal expression of the DUX4 gene in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD), a prevalent inherited human myopathy, develops following a complex interplay of genetic and epigenetic events. FSHD1, the more frequent genetic form, is associated with: (1) deletion of an integral number of 3.3 Kb (D4Z4) repeated elements at the chromosomal region 4q35, (2) a specific 4q35 subtelomeric haplotype denominated 4qA, and (3) decreased methylation of cytosines at the 4q35-linked D4Z4 units. FSHD2 is most often caused by mutations at the SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain 1) gene, on chromosome 18p11.32. FSHD2 individuals also carry the 4qA haplotype and decreased methylation of D4Z4 cytosines. Each D4Z4 unit contains a copy of the retrotransposed gene DUX4 (double homeobox containing protein 4). DUX4 gene functionality was questioned in the past because of its pseudogene-like structure, its location on repetitive telomeric DNA sequences (i.e. junk DNA), and the elusive nature of both the DUX4 transcript and the encoded protein, DUX4. It is now known that DUX4 is a nuclear-located transcription factor, which is normally expressed in germinal tissues. Aberrant DUX4 expression triggers a deregulation cascade inhibiting muscle differentiation, sensitizing cells to oxidative stress, and inducing muscle atrophy. A unifying pathogenic model for FSHD emerged with the recognition that the FSHD-permissive 4qA haplotype corresponds to a polyadenylation signal that stabilizes the DUX4 mRNA, allowing the toxic protein DUX4 to be expressed. This working hypothesis for FSHD pathogenesis highlights the intrinsic epigenetic nature of the molecular mechanism underlying FSHD as well as the pathogenic pathway connecting FSHD1 and FSHD2. Pharmacological control of either DUX4 gene expression or the activity of the DUX4 protein constitutes current potential rational therapeutic approaches to treat FSHD.

Respiratory muscle dysfunction in facioscapulohumeral muscular dystrophy.

Respiratory insufficiency in facioscapulohumeral muscular dystrophy has rarely been studied. We compared two age- and sex-matched groups of 29 patients, with and without respiratory dysfunction. Tests in the 29 patients with respiratory dysfunction suggested predominant expiratory muscle dysfunction, leading to ineffective cough in 17 patients. Supine and upright vital capacities were not different (P = 0.76), suggesting absence of diaphragmatic dysfunction. By stepwise regression, only expiratory reserve volume correlated with the Walton and Gardner-Medwin score (R(2) = 0.503; P = 0.001). Compared to controls, patients with respiratory dysfunction had higher values for the Walton and Gardner-Medwin score (6.1 ± 1.9 vs. 3.2 ± 1.2; P <0.0001) and body mass index (26.9 ± 6.0 vs. 22.9 ± 4.0 kg/m(2); P = 0.003) and a smaller number of D4Z4 allele repeats (4.8 ± 1.6 vs. 5.7 ± 1.8; P = 0.05). Mechanical ventilation was required eventually in 20 patients, including 14 who were wheelchair bound. Three patients had acute respiratory failure requiring mechanical ventilation; 16 patients had poor airway clearance, including 10 with sleep apnea syndrome, responsible in 7 for chronic hypercapnia. Two patients presented isolated severe sleep apnea syndrome. Respiratory dysfunction in facioscapulohumeral muscular dystrophy is predominantly related to expiratory muscle weakness. Respiratory function and cough effectiveness should especially be monitored in patients with severe motor impairment and high body mass index.

Avaliação dos resultados da artrodese da articulação escapulotorácica no tratamento da escápula alada na distrofia fascioescapulumeral / Evaluation of scapulothoracic arthrodesis results in the treatment of winged scapula in facioscapulohumeral dystrophy

OBJETIVO: Avaliar a técnica cirúrgica da artrodese escapulotorácica na distrofia fascioescapulumeral (DFEU), analisando os resultados e as complicações pós-operatórias. MÉTODOS: No período de fevereiro de 1992 a fevereiro de 2006 foram realizadas oito artrodeses escapulotorácicas em cinco pacientes no Departamento de Ortopedia e Traumatologia da Faculdade de Ciências Médicas da Santa Casa de São Paulo (DOT-FCM-SCSP). Os critérios para indicação cirúrgica foram: dor, déficit funcional do membro acometido, fadiga muscular e deformidade estética. Na técnica cirúrgica empregada para a artrodese foi realizada a fixação da escápula à parede torácica por meio de amarrilho com fios de poliéster n° 5, uma placa metálica estreita e fina, além de colocação de enxerto esponjoso autólogo. RESULTADOS: O seguimento médio dos pacientes foi de 124 meses. Na comparação da amplitude de movimentos pré e pós-operatórios, notou-se melhora na elevação, mantida a rotação lateral, com o UCLA no período pré-operatório variando de 7 a 11 e pós-operatório de 29 a 33. Dentre as complicações, encontraram-se dois casos de pneumotórax, um caso de soltura do material de síntese e um caso de ausência de consolidação óssea. COMENTÁRIO: Obtida consolidação da artrodese em seis casos, além da melhora da dor e elevação. Dois casos foram reoperados, sendo um devido à quebra do material e o outro, à não consolidação. Todos evoluíram para consolidação.

OBJECTIVE: To evaluate the surgical scapulothoracic arthrodesis technique in facioscapulohumeral dystrophy (FSHD) by analyzing post-op results and complications. METHODS: from February 1992 to February 2006, eight scapulothoracic arthrodesis procedures were performed in five patients at the Orthopedics and Traumatology Department of the Medical Sciences School at the Santa Casa Hospital of São Paulo (DOT-FCM-SCSP). The criteria for surgical indication were pain, functional deficit of the limb involved, muscular fatigue, and esthetic deformity. The surgical technique used for the arthrodesis fixated the scapula to the thoracic wall by tying a narrow, slim plate with No. 5 polyester threads and placing an autologous cancellous bone graft. RESULTS: Mean follow-up of the patients was of 124 months. Comparing the range of movement before and after surgery, the authors observed an improvement in raising, lateral rotation being kept, with the pre-op UCLA ranging from 7 to 11, and the post-op UCLA ranging from 29 to 33. Complications included two cases of pneumothorax; one case of the detachment of synthesis material, and one case of lack of bone fusion. COMMENT: Arthrodesis fusion was achieved in six cases, besides improvement in pain and raising. Two cases were reoperated on, one of them due to breakage of the material and another one due to lack of fusion. All cases evolved on to fusion.