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Werner Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for Werner syndrome include atypical Werner syndrome (early age of onset at early 20s or earlier, faster rate of progression; normal WRN proteins, heterozygous pathogenic missense variants in LMNA in 15% of cases), mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL; progeroid features, lipodystrophy, characteristic facial features, sensorineural hearing loss; absence of ocular cataracts), mandibulo-acral dysplasia (MAD; short stature, type A lipodystrophy, loss of fat in the extremities but accumulation of fat in the neck and trunk, thin, hyperpigmented skin, partial alopecia, prominent eyes, convex nasal ridge, tooth loss, micrognathia, retrognathia, and short fingers; biallelic pathogenic variants in LMNA, and zinc metalloproteinase ZMPSTE24), Hutchinson−Gilford progeria syndrome (HGPS, progeria of childhood; accelerated aging, profound failure to thrive during the first year, characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, progressive joint contractures, bone changes, abnormal tightness and/or small soft outpouchings of the skin over the abdomen and upper thighs during the second to third year; severe atherosclerosis; death due to cardiac or cerebrovascular disease between age 6 and 20 years; average life span of approximately 14.6 years; autosomal dominant disorder due to LMNA pathogenic variant c.1824C>T), early-onset type 2 diabetes with secondary complications (mimicking some features of Werner syndrome), myotonic dystrophy type 1 or myotonic dystrophy type 2 (young adult-onset cataracts, muscle wasting in adults), scleroderma, mixed connective tissue disorders, and lipodystrophy (similar skin features), Charcot−Marie−tooth hereditary neuropathy or familial leg ulcers of juvenile onset (distal atrophy and skin ulcerations in the absence of other manifestations characteristic of Werner syndrome), Rothmund−Thomson syndrome (RTS; autosomal recessive disorder due to pathogenic variants in RECQL4), BLM (increased sister chromatid exchange; autosomal recessive disorder due to pathogenic variants in BLM), Li−Fraumeni syndrome (multiple cancers, absence of juvenile-onset cataracts, autosomal dominant disorder due to pathogenic variants in TP53), Flynn−Aird syndrome (cataracts, skin atrophy and ulceration; neurologic abnormalities), brachiooculofacial syndrome (premature graying in adults; strabismus, coloboma, and microphthalmia; dysmorphic facial features; autosomal dominant disorder due to TFAP2A pathogenic variants), SHORT syndrome (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay; progeria-like facies and lipodystrophy, type 2 diabetes mellitus, cataracts and glaucoma; autosomal dominant disorder due to pathogenic variants in PIK3R1 [1,18,19].
KCTD1 and Scalp-Ear-Nipple (‘Finlay–Marks’) syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chains
Published in Ophthalmic Genetics, 2023
Dongmao Wang, Paul Trevillian, Stephen May, Peter Diakumis, Yanyan Wang, Deb Colville, Melanie Bahlo, Una Greferath, Erica Fletcher, Barbara Young, Heather G. Mack, Judy Savige
KCTD1 is a transcriptional repressor or activator of TFAP2α, TFAP2β, and TFAP2γ (10). Mutations in the TFAP2 genes inform our understanding of the mechanisms underlying KCTD1 mutations. TFAP2A mutations result in the Branchio-Oculo-Facial syndrome (OMIM 113,620), with branchial and periauricular skin defects, and sometimes microophthalmia or anopthalmia, coloboma, hypertelorism, cleft lip, cleft palate, prominent ears, and hearing loss (11). Renal cysts and aplasia may occur. Mutations in the TFAP2B gene result in Char syndrome (12) (OMIM 169,100), with facial abnormalities, patent ductus arteriosus, and aplasia/hypoplasia of the fifth finger middle phalanges (13) together with hearing loss, multiple nipples (14), syndactyly (15,16), and sometimes myopia (17), strabismus (squint) (17) and coloboma. There may be supernumerary nipples (14), and absent second and third molar teeth (17,18). Mice with a targeted loss of Tfap2β have multiple renal cysts (19). The effects of TFAP2C on apoptosis and Wnt signalling may also contribute to kidney cyst formation (20).
Understanding host responses to equine encephalitis virus infection: implications for therapeutic development
Published in Expert Review of Anti-infective Therapy, 2022
Kylene Kehn-Hall, Steven B. Bradfute
A recent VEEV nsP3 interactome study identified 160 putative host interacting proteins, including eukaryotic initiation factor 2 subunit 2 (eIF2S2) and transcription factor AP-2 alpha (TFAP2A) which were validated for their importance in VEEV production through siRNA studies [83]. eIF2S2 was found to facilitate VEEV genomic RNA translation, but not translation of the subgenomic RNA [83]. Citalopram HBr and Z-VEID-FMK, inhibitors of TFAP2A, and Tomatidine, a small molecule inhibitor of eIF2S2, decreased VEEV production by >10 fold. Citalopram HBr, Z-VEID-FMK, and Tomatidine also suppressed EEEV replication.
Progressive Loss of Retinal Ganglion Cells in Activating Protein-2β Neural Crest Cell Knockout Mice
Published in Current Eye Research, 2021
Aftab Taiyab, Anthony Saraco, Monica Akula, Paula Deschamps, Alexander K. Ball, Trevor Williams, Judith A. West-Mays
We have previously shown that in the developing murine eye, the transcription factor activating protein 2 (AP-2) is highly expressed in the POM. In particular, two family members, AP-2β (encoded by the gene Tfap2b) and AP-2α (encoded by Tfap2a) are expressed in the POM. At embryonic day 8, (E8) both AP-2β and AP-2α showed overlapping expression in the POM, but by E11 this pattern began to diverge and by E15.5, the POM expressed predominantly AP-2β and very little AP-2.5,6 Thus, AP-2β appears to be the more significant AP-2 family member in the developing POM. Mice with germline deletions of AP-2β (AP-2β−/-) die soon after birth and as a result, full eye development could not be examined.7 Thus, to circumvent the lethality of a germline deletion of the AP-2β transcription factor, our laboratory employed Wnt1-Cre, a Cre well known to be expressed in cranial NCC that contributes, in part, to the development of ocular angle structures and cornea,3 to conditionally delete AP-2β exclusively from the cranial NCCs that contribute to the POM.6 These mice, termed the AP-2β NCC KO, exhibited multiple defects in the developing anterior segment. This included a lack of formation of the corneal endothelium and an anterior iris that was completely adhered to the posterior corneal stroma, resulting in a complete closure of the iridocorneal angle, and absence of formation of the trabecular meshwork and Schlemm’s canal normally found in this region.8 The angle closure was accompanied by a significant increase in intraocular pressure (IOP) in the mutant mice. Importantly, we were also able to demonstrate that the mutant mice exhibited a significant decrease in the number of RGCs by 2–3 months of age, along with evidence of optic nerve degeneration.6