Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033377 (prolapse)
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A translocation breakpoint 171 kb 5' of the transcription start of FOXL2 causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) and associated premature ovarian failure. The breakpoint falls within another gene, MRPS22, that has been sequenced in 500 kb of continuous DNA. MRPS22 encodes 20 exons and a number of alternative transcripts. Three CpG islands (>91% identical) are followed by noncoding exons 4-12 and coding exons 13-20. The 3'UTR extends into the 3'UTR of COPB2. Based on the sequence, three reported translocations that cause BPES all fall within intron 6 of MRPS22. Comparisons reveal conserved segments in introns 6, 11, and 12 of human and mouse. Notably intron 11 sequence is also deleted in goat PIS syndrome (which combines craniofacial defects, female infertility, and XX sex reversal). The conserved sequences are candidates for models in which they are distant enhancers or otherwise affect higher order chromatin structure to impose long-range cis regulation of FOXL2 expression.
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PMID:FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences. 1508 Nov 6

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (POF), has recently been ascribed to mutations in the forkhead transcription factor 2 (FOXL2) gene. In this work, we reveal a novel insertion mutation in the 3'UTR of the FOXL2 gene in a big Chinese family which is to our knowledge the first BPES (type II) family reported in China. It is the first time that a 3'UTR mutation in the FOXL2 gene has ever been found to demonstrate a close correlation between genotype and BPES. Our result gains a greater insight into the function of 3'UTR in the FOXL2 gene.
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PMID:A novel insertion mutation in the FOXL2 gene is detected in a big Chinese family with blepharophimosis-ptosis-epicanthus inversus. 1545 Apr

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant syndrome of eyelid malformations with (type I) or without (type II) associated premature ovarian failure. Multiple mutations in the exon and the putative core promoter region of FOXL2 gene encoding a putative forkhead transcription factor have been linked to this disease. To examine whether FOXL2 gene mutations contribute to BPES in the Chinese patient population, we screened 33 patients from 18 Chinese families with BPES of unknown types, together with 57 healthy individuals, including 27 relatives of the affected families. Genomic DNA was extracted from the participants' peripheral blood leukocytes, and amplified by polymerase chain reaction for various regions of the FOXL2 gene, followed by sequencing analysis. Ten mutations in the FOXL2 gene were detected: four were previously reported (g.1041_1042insC, g.1366_1367insT, g.909_938dup30, and g.900_929dup30), and six were novel ones (g.406T>A, g.-14G>A, g.1108_1109insC, g.2577C>T, g.1987C>A, and g.1002C>G). Among them, mutations in the coding region for the polyalanine tract, as well as novel mutations in the core promoter, the 3'-UTR, and in the forkhead domain were identified. Our results expanded the spectrum of FOXL2 mutations in BPES and provided additional valuable genetic information for this rare disease.
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PMID:Mutations of the transcription factor FOXL2 gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. 1937 Dec 27

Myotonic Dystrophy Type 1 (DM1) is the most common worldwide autosomal dominant muscular dystrophy due to polynucleotide [CTG]( n ) triplet expansion located on the 3'UTR of chromosome 19q13.3. A toxic gain-of-function of abnormally stored RNA in the nuclei of affected cells is assumed to be responsible for several clinical features of the disease. It plays a basic role in deregulating RNA binding protein levels and in several mRNA splicing processes of several genes, thus leading to the multisystemic features typical of DM1. In DM1, the musculoskeletal apparatus, heart, brain, eye, endocrine, respiratory and gastroenteric systems are involved with variable levels of severity. DM1 onset can be congenital, juvenile, adult or late. DM1 can be diagnosed on the grounds of clinical presentation (distal muscular atrophy and weakness, grip and percussion myotonia, ptosis, hatchet face, slurred speech, rhinolalia), EMG myotonic pattern, EKG (such as AV-blocks) or routine blood test abnormalities (such as increased CK values or hypogamma-globulinemia) and history of cataract. Its confirmation can come by DNA analysis. At present, only symptomatic therapy is possible and is addressed at correcting hormonal and glycemic balance, removing cataract, preventing respiratory failure and, above all, major cardiac disturbances. Efficacious therapies targeted at the pathogenic mechanism of DM1 are not yet available, while studies that seek to block toxic RNA intranuclear storage with specific molecules are still ongoing.
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PMID:Myotonic Dystrophy Type 1 or Steinert's disease. 2241 Dec 47

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5' UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.
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PMID:Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy. 3241 82