phenylephrine-hydrochloride and Muscular-Dystrophy--Facioscapulohumeral

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4.

Topics: Choanal Atresia; CpG Islands; DNA Methylation; Epigenesis, Genetic; Face; Homeodomain Proteins; Humans; Microphthalmos; Muscle Weakness; Muscular Dystrophy, Facioscapulohumeral; Nose; Primary Immunodeficiency Diseases; Protein Processing, Post-Translational; Tandem Repeat Sequences

It has very recently become clear that the epigenetic modifier SMCHD1 has a role in two distinct disorders: facioscapulohumoral muscular dystrophy (FSHD) and Bosma arhinia and micropthalmia (BAMS). In the former there are heterozygous loss-of-function mutations, while both gain- and loss-of-function mutations have been proposed to underlie the latter. These findings have led to much interest in SMCHD1 and how it works at the molecular level. We summarise here current understanding of the mechanism of action of SMCHD1, its role in these diseases, and what has been learnt from study of mouse models null for Smchd1 in the decade since the discovery of SMCHD1.

Topics: Animals; Choanal Atresia; Chromosomal Proteins, Non-Histone; DNA Methylation; Epigenesis, Genetic; Heterozygote; Humans; Mice; Microphthalmos; Muscular Dystrophy, Facioscapulohumeral; Mutation; Nose

Topics: Chromosomal Proteins, Non-Histone; Congenital Abnormalities; Gene Expression Regulation; Homeodomain Proteins; Humans; Muscular Dystrophy, Facioscapulohumeral; Nose; Transcription Factors

Structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1) is an architectural factor critical for X-chromosome inactivation (XCI) and the repression of select autosomal gene clusters. In mice, homozygous nonsense mutations in

Topics: Animals; Cadherins; Choanal Atresia; Chromosomal Proteins, Non-Histone; Codon, Nonsense; Female; Genes, Lethal; Humans; Mice; Microphthalmos; Muscular Dystrophy, Facioscapulohumeral; Nose; Protocadherins; Transcriptome; X Chromosome Inactivation

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.

Topics: Cells, Cultured; Cellular Reprogramming; Choanal Atresia; Chromosomal Proteins, Non-Histone; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; HCT116 Cells; HEK293 Cells; Homeodomain Proteins; Humans; Male; Microphthalmos; Microsatellite Repeats; Muscular Dystrophy, Facioscapulohumeral; Nose

Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (. Examination of. The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.

Topics: Adenosine Triphosphatases; Choanal Atresia; Chromosomal Proteins, Non-Histone; DNA Methylation; Female; Genetic Variation; Humans; Male; Microphthalmos; Muscular Dystrophy, Facioscapulohumeral; Mutation; Mutation, Missense; Nose; Protein Domains

Structural maintenance of chromosomes flexible hinge domain-containing 1 (Smchd1) plays important roles in epigenetic silencing and normal mammalian development. Recently, heterozygous mutations in

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Amino Acid Sequence; Animals; Choanal Atresia; Chromosomal Proteins, Non-Histone; Crystallography, X-Ray; Eye Diseases; Humans; Mice; Microphthalmos; Muscular Dystrophy, Facioscapulohumeral; Mutation, Missense; Nose; Protein Conformation; Protein Domains; Sequence Homology; Xenopus laevis

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

Topics: Animals; Cell Line; Child, Preschool; Choanal Atresia; Chromosomal Proteins, Non-Histone; Epigenesis, Genetic; Female; Genetic Predisposition to Disease; Humans; Male; Mice; Mice, Inbred C57BL; Microphthalmos; Muscular Dystrophy, Facioscapulohumeral; Mutation, Missense; Nose; Xenopus laevis