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Cellular Physiology and Biochemistry :... 2018Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an...
BACKGROUND/AIMS
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). Functional study of novel mutations is especially critical for female patients, as it may allow the prediction of infertility and early planning of an appropriate therapy.
METHODS
A clinical and molecular genetic investigation was performed in all members of a Chinese family with BPES. Genomic DNA was extracted, and the FOXL2 coding region was sequenced. Subcellular localization was performed by confocal microscopy. Transactivation studies were performed by real-time PCR, dual luciferase reporter assays and electrophoretic mobility shift assays.
RESULTS
A novel deletion mutation (C.634_641 del, CCCATGC) between the forkhead domain and the polyalanine domain was found, resulting in a frameshift mutation and a truncated protein. Functional studies showed a strong cytoplasmic mislocalization and abnormal transactivation activity, implying a type I kind mutation with a large chance of infertility.
CONCLUSION
This study identifies that this mutation indicates the probability of developing into POF and shows the importance and necessity of early recognition of BPES type through mutation testing for female patients. Prompt personalized therapy and follow-up is of great clinical significance for female patients carrying this kind of mutation.
Topics: Base Sequence; Blepharophimosis; Child; Cytoplasm; DNA; Electrophoretic Mobility Shift Assay; Female; Forkhead Box Protein L2; Frameshift Mutation; Humans; Male; Microscopy, Confocal; Pedigree; Sequence Analysis, DNA; Sequence Deletion; Skin Abnormalities; Transcriptional Activation; Urogenital Abnormalities
PubMed: 29339661
DOI: 10.1159/000486358 -
The Journal of Biological Chemistry Feb 2017Recent genome-wide studies found that patients with hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic...
Recent genome-wide studies found that patients with hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels suffer from aufman culocerebrofacial yndrome (KOS, also reported as blepharophimosis-ptosis-intellectual disability syndrome). The primary cause of KOS is autosomal recessive mutations in the gene However, to date, there are no studies that have determined the cellular or enzymatic function of UBE3B. Here, we report that UBE3B is a mitochondrion-associated protein with omologous to the 6-AP erminus (HECT) E3 ubiquitin ligase activity. Mutating the catalytic cysteine (C1036A) or deleting the entire HECT domain (amino acids 758-1068) results in loss of UBE3B's ubiquitylation activity. Knockdown of UBE3B in human cells induces changes in mitochondrial morphology and physiology, a decrease in mitochondrial volume, and a severe suppression of cellular proliferation. We also discovered that UBE3B interacts with calmodulin via its N-terminal isoleucine-glutamine (IQ) motif. Deletion of the IQ motif (amino acids 29-58) results in loss of calmodulin binding and a significant increase in the ubiquitylation activity of UBE3B. In addition, we found that changes in calcium levels disrupt the calmodulin-UBE3B interaction. These studies demonstrate that UBE3B is an E3 ubiquitin ligase and reveal that the enzyme is regulated by calmodulin. Furthermore, the modulation of UBE3B via calmodulin and calcium implicates a role for calcium signaling in mitochondrial protein ubiquitylation, protein turnover, and disease.
Topics: Amino Acid Sequence; Calmodulin; Cell Line, Tumor; Cell Proliferation; Gene Knockdown Techniques; Humans; Mitochondria; Sequence Homology, Amino Acid; Ubiquitin-Protein Ligases
PubMed: 28003368
DOI: 10.1074/jbc.M116.766824 -
Frontiers in Genetics 2024Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare inherited disorder. This study was aimed to identify and functionally validate variants in...
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare inherited disorder. This study was aimed to identify and functionally validate variants in two Chinese families with BPES. The proband and his family members were subjected to whole-exome sequencing to identify disease-associated variants. Several bioinformatic tools were used to computationally predict altered proteins. functional assays were conducted by transfecting wild-type and mutant cDNAs into HEK-293 cells, followed by subcellular localization assays, luciferase reporter gene assays, and quantitative real-time polymerase chain reaction. The clinical features of BPES, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, were present in all affected patients. Two novel mutations were detected, c.292T>A and c.383G>T. Whole-exome sequencing analysis and prediction software suggested that these mutations were pathogenic. Functional studies showed that these two point mutations decreased FOXL2 protein expression, resulting in subcellular mislocalization and aberrant transcriptional activity of the steroidogenic acute regulatory protein gene promoter. Our results add to the current understanding of known variants in, and our experiments provide reference data and insights into the etiology of BPES. Further studies are needed to identify the possible mechanisms underlying the action of this mutation on the development of BPES.
PubMed: 38410153
DOI: 10.3389/fgene.2024.1343411 -
The Eurasian Journal of Medicine Jun 2020Nablus mask-like facial syndrome (NMLFS) is defined by distinctive craniofacial appearance including tight-appearing glistening facial skin, blepharophimosis,...
Nablus mask-like facial syndrome (NMLFS) is defined by distinctive craniofacial appearance including tight-appearing glistening facial skin, blepharophimosis, telecanthus, severe arched eyebrows, flat and broad nose, long philtrum, distinctive ears, unusual hair patterns, mild developmental delay and "happy" disposition. We aim to report a 7-year-old boy diagnosed with NMLFS and moderate developmental delay. Literature emphasis that Intellectual Disability is common in this syndrome though it has been diagnosed to only a few people worldwide.
PubMed: 32612438
DOI: 10.5152/eurasianjmed.2020.18448 -
Open Life Sciences 2021Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal-dominant genetic disorder, and mutations in the forkhead box L2 () gene are one of the...
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal-dominant genetic disorder, and mutations in the forkhead box L2 () gene are one of the major genetic causes. As this study shows, there are many patients with BPES who do not have mutations, as the screening results in all family members were negative. Using whole-exome sequence analysis, we discovered another possible mutational cause of BPES in integrin subunit beta 5 (). The mutation (c.608T>C, p.Ile203Thr) appears in the base sequence of all BPES patients in this family, and it appears to be a three-generation-inherited mutation. It can cause changes in base sequence and protein function, and there may be cosegregation of disease phenotypes. is located on the long arm of chromosome three (3q21.2) and is close to the known pathogenic gene (3q23). This study is the first to report mutations in BPES, and we speculate that it may be directly involved in the pathogenesis of BPES or indirectly through the regulation of .
PubMed: 34966851
DOI: 10.1515/biol-2021-0129 -
Journal of Pediatric Genetics Dec 2014The prevalence of congenital ocular malformations has been described to vary from 0.04 to 6.8 per 10,000 live births. The nuclear mutations identified in chronic...
The prevalence of congenital ocular malformations has been described to vary from 0.04 to 6.8 per 10,000 live births. The nuclear mutations identified in chronic progressive external ophthalmoplegia harbor multiple mtDNA deletions that include POLG mutations, PEO1 mutations, OPA1 mutations and RRM2B mutations. In Kearns-Sayre syndrome, the spontaneous mitochondrial deletions vary from 1.3 to 8.0 kb subunits of the oxidative phosphorylation enzymes and several t-RNA genes are affected. Oculopharyngeal muscle dystrophy is both autosomal dominant and recessive form. Congenital fibrosis of extraocular muscles (CFEOM) 1 has mutations in KIF21A on chromosome 12 with TUBB3 mutation also being seen. CFEOM 2 is an autosomal recessive, genetically distinct entity with homozygous mutations in PHOX2A. CFEOM 3 is autosomal dominant heterozygous missense mutations in TUBB3. Most cases of Mobius syndrome are sporadic with familial cases being autosomal dominant, autosomal recessive or X-linked recessive inheritance. Genetic testing has shown abnormalities involving chromosome 1 and 13. Presynaptic congenital myasthenic syndrome is caused by ChAT (choline acetyltransferase) mutation. Two loci have been found for myotonic dystrophy (DM). DM1, which is associated with trinucleotide expansion on chromosome 19q13.3 and DM2 which is associated with CCTG tetranucleotide expansion at 3q21. Blepharophimosis is caused by mutations in the FOXL2 gene 49 located at chromosome 3q23. Lymphedema-distichiasis is an autosomal dominant disorder caused by mutations in the FOXC2 gene.
PubMed: 27625884
DOI: 10.3233/PGE-14109 -
BMC Ophthalmology Nov 2018Amblyopia is a main concern in children undergoing frontalis sling surgery for repairing congenital ptosis. This study aimed to evaluate factors related to amblyopia in...
BACKGROUND
Amblyopia is a main concern in children undergoing frontalis sling surgery for repairing congenital ptosis. This study aimed to evaluate factors related to amblyopia in children undergoing frontalis sling surgery.
METHODS
IRB-approved retrospective review of children under the age of 12 who received frontalis sling surgery. Preoperative demographic data, strabismus, margin reflex distance 1 (MRD1), lid fissure height, sling type, refraction errors, surgical outcome and amblyopia were evaluated.
RESULTS
This study included 48 eyelid procedures performed in 38 patients. Median age was 4.0 years. Etiology was congenital ptosis in 42 eyes (87.5%) and blepharophimosis in 6 eyes (12.5%). Mersilene mesh was the sling material used in 36 eyes (75%), silicone in 6 eyes (12.5%), and polytetrafluoroethylene (PTFE) in 6 eyes (12.5%). Mean duration of follow-up was 27.8 ± 25.0 months (range, 3 to 128 months). Amblyopia was observed in 17 eyes (35.4%) at the final follow-up. Factors significantly associated with final amblyopia included blepharophimosis (p = 0.017), preoperative MRD1 ≤ - 1.0 mm (p = 0.038), preoperative lid fissure ≤4.5 mm (p = 0.035), preoperative anisometropia (spherical equivalent) (p = 0.011), and postoperative astigmatism (p = 0.026).
CONCLUSIONS
Study results suggest that blepharophimosis, preoperative MRD1 ≤ - 1.0 mm, preoperative lid fissure ≤4.5 mm, preoperative anisometropia (spherical equivalent), and postoperative astigmatism are associated with amblyopia after frontalis sling surgery in patients with congenital ptosis.
Topics: Amblyopia; Anisometropia; Astigmatism; Blepharoptosis; Child; Child, Preschool; Eyelids; Female; Humans; Male; Oculomotor Muscles; Postoperative Complications; Retrospective Studies
PubMed: 30463547
DOI: 10.1186/s12886-018-0962-4 -
European Journal of Human Genetics :... Sep 2015KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and...
KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.
Topics: Blepharophimosis; Child, Preschool; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Mutational Analysis; Diagnosis, Differential; Exome; Exons; Facies; Female; Gene Expression; Genetic Association Studies; Genotype; Heart Defects, Congenital; Histone Acetyltransferases; Humans; Intellectual Disability; Joint Instability; Kidney; Male; Mutation; Patella; Phenotype; Psychomotor Disorders; Scrotum; Severity of Illness Index; Urogenital Abnormalities
PubMed: 25424711
DOI: 10.1038/ejhg.2014.248 -
Journal of Medical Genetics Sep 1997We have evaluated a 3 2/12 year old girl who presented with unilateral blepharophimosis, ptosis of the eyelid, and mental retardation. Additional dysmorphic features... (Review)
Review
We have evaluated a 3 2/12 year old girl who presented with unilateral blepharophimosis, ptosis of the eyelid, and mental retardation. Additional dysmorphic features include microcephaly, high, narrow forehead, short stubby fingers, and adduction of the right first toe. Cytogenetic analysis showed an unbalanced karyotype consisting of 46,XX,add(7)(q+) that was de novo in origin. Fluorescence in situ hybridisation (FISH) using microdissected library probe pools from chromosomes 1,2,3,7, and 3q26-qter showed that the additional material on 7q was derived from the distal end of the long arm of chromosome 3. Our results indicate that the patient had an unbalanced translocation, 46,XX,der(7)t(3;7)(q26-qter;q+) which resulted in trisomy for distal 3q. All currently reported cases of BPES (blepharophimosis-ptosis-epicanthus inversus syndrome) with associated cytogenetic abnormalities show interstitial deletions or balanced translocations involving 3q22-q23 or 3p25.3. Our patient shares similar features to BPES, except for the unilateral ptosis and absence of epicanthus inversus. It is possible that our patient has a contiguous gene defect including at least one locus for a type of blepharophimosis, further suggesting that multiple loci exist for eyelid development.
Topics: Adult; Blepharophimosis; Blepharoptosis; Child, Preschool; Chromosomes, Human, Pair 3; Female; Humans; In Situ Hybridization, Fluorescence; Infant; Infant, Newborn; Intellectual Disability; Male; Pregnancy; Trisomy
PubMed: 9321768
DOI: 10.1136/jmg.34.9.772 -
Neurology India 2023We report a 24-year-old male with blepharophimosis, psychomotor retardation, brachycephaly, microstomia, immobile face, high arched palate, single palmar crease,...
We report a 24-year-old male with blepharophimosis, psychomotor retardation, brachycephaly, microstomia, immobile face, high arched palate, single palmar crease, kyphoscoliosis, talipes equinovarus, inguinal hernia, pyloric stenosis, recurrent infections, bilateral camptodactyly, wide-set eyes, decreased muscle mass, hypotonia, exotropia, and ptosis in the left eye, growth retardation, multiple congenital contractures, and hyporreflexia. Contractures improved with aging, but intellectual disability and blepharophimosis remained. He also presented epilepsy, outbursts of laughter, and predisposition to drug adverse effects (skin lesions with carbamazepine and secondary parkinsonism).
Topics: Male; Humans; Young Adult; Adult; Blepharophimosis; Syndrome; Abnormalities, Multiple; Contracture; Intellectual Disability
PubMed: 37635513
DOI: 10.4103/0028-3886.383870