Smaragda Kamakari - Academia.edu (original) (raw)

Papers by Smaragda Kamakari

Doctoral thesis, UCL (University College London)., 1994

Springer eBooks, 1996

Deletions or loss of heterozygosity in certain regions of the long arms of human chromosomes 6 an... more Deletions or loss of heterozygosity in certain regions of the long arms of human chromosomes 6 and 10 have been reported over the last few years in several types of malignancies; more specifically, region 6ql6.3-q21 is frequently deleted in patients with acute lymphoblastic leukemia1 (ALL) and the same region, as well as 6q25-qter are often deleted in patients with Non-Hodgkins lymphoma1; loss of heterozygosity in both these regions has also, been documented in breast2 and ovarian3 cancer. In addition, loss of heterozygosity within the 10q23-24 region has been reported in patients with prostate cancer4 and patients with glioblastoma multiforme5. These observations suggest the presence of tumor-suppressor gene(s) in these regions and, therefore, detailed physical mapping may lead to the identification and subsequent isolation of such genes.

bioRxiv (Cold Spring Harbor Laboratory), Oct 25, 2019

Missing heritability in human diseases represents a major challenge. Although whole-genome sequen... more Missing heritability in human diseases represents a major challenge. Although whole-genome sequencing enables the analysis of coding and non-coding sequences, substantial costs and data storage requirements hamper its large-scale use to (re)sequence genes in genetically unsolved cases. The ABCA4 gene implicated in Stargardt disease (STGD1) has been studied extensively for 22 years, but thousands of cases remained unsolved. Therefore, single molecule molecular inversion probes were designed that enabled an automated and cost-effective sequence analysis of the complete 128-kb ABCA4 gene. Analysis of 1,054 unsolved STGD and STGD-like probands resulted in bi-allelic variations in 448 probands. Twenty-seven different causal deep-intronic variants were identified in 117 alleles. Based on in vitro splice assays, the 13 novel causal deep-intronic variants were found to result in pseudo-exon (PE) insertions (n=10) or exon elongations (n=3). Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions that were accompanied by flanking exon deletions. Structural variant analysis revealed 11 distinct deletions, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Integrated complete gene sequencing combined with transcript analysis, identified pathogenic deep-intronic and structural variants in 26% of bi-allelic cases not solved previously by sequencing of coding regions. This strategy serves as a model study that can be applied to other inherited diseases in which only one or a few genes are involved in the majority of cases.

Clinical Endocrinology, 2009

SummaryIntroduction Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant heredita... more SummaryIntroduction Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder associated with mutations of the MEN1 gene and characterized by the combined occurrence of tumours of the parathyroid glands, the pancreatic islet cells and the anterior pituitary.Aim To identify MEN1 gene mutations and characterize clinical manifestations in Greek patients with MEN1.Patients and methods We studied four unrelated index patients with MEN1, 17 relatives and 100 control subjects. Among the relatives, seven were clinically and/or biochemically affected, while 10 were unaffected. DNA extraction, polymerase chain reaction (PCR) and direct sequencing of the MEN1 exons 2–10 and exon/intron boundaries were performed according to standard procedures.Results We identified novel MEN1 gene mutations in three out of four index patients (75%) and in all affected (100%) relatives. Novel mutations included: a frameshift mutation in exon 4 (c.684_685insG) at codon 229 (index patient A); a frameshift mutation in exon 8 (c.1160_1170dupAGGAGCGGCCG) involving codons 387–390 (index patient B); and a missense mutation in exon 4 (c.776T > C), which substitutes leucine with proline at codon 259 (L259P) (index patient C). In the fourth index patient, a common polymorphism (D418D) was detected.Conclusions This is the first report to reveal a high prevalence of novel MEN1 gene mutations among Greek MEN1 patients with apparent absence of genotype–phenotype correlation. Because of the small number of patients examined, the high prevalence detected might be a chance phenomenon.

Investigative Ophthalmology & Visual Science, 2009

Investigative Ophthalmology & Visual Science, 2007

Investigative Ophthalmology & Visual Science, 2008

Journal of Ophthalmology, 2018

Aim. To evaluate the frequency and pattern of disease-associated mutations of ABCA4 gene among Gr... more Aim. To evaluate the frequency and pattern of disease-associated mutations of ABCA4 gene among Greek patients with presumed Stargardt disease (STGD1). Materials and Methods. A total of 59 patients were analyzed for ABCA4 mutations using the ABCR400 microarray and PCR-based sequencing of all coding exons and flanking intronic regions. MLPA analysis as well as sequencing of two regions in introns 30 and 36 reported earlier to harbor deep intronic disease-associated variants was used in 4 selected cases. Results. An overall detection rate of at least one mutant allele was achieved in 52 of the 59 patients (88.1%). Direct sequencing improved significantly the complete characterization rate, that is, identification of two mutations compared to the microarray analysis (93.1% versus 50%). In total, 40 distinct potentially disease-causing variants of the ABCA4 gene were detected, including six previously unreported potentially pathogenic variants. Among the disease-causing variants, in this cohort, the most frequent was c.5714+5G>A representing 16.1%, while p.Gly1961Glu and p.Leu541Pro represented 15.2% and 8.5%, respectively. Conclusions. By using a combination of methods, we completely molecularly diagnosed 48 of the 59 patients studied. In addition, we identified six previously unreported, potentially pathogenic ABCA4 mutations.

51 Armaan Akbar Physical Science and Engineering Biomimetic Small Diameter Vascular Graft Armaan ... more 51 Armaan Akbar Physical Science and Engineering Biomimetic Small Diameter Vascular Graft Armaan Akbar; Matteo Solazzo; Paulo Gonzalez; Daniel Jacobs; Michael Luketich; Rich Hoff, MA; Antonio D'Amore, PhD; William Wagner, PhD Current methods utilized in coronary bypass include the use of synthetic as well as biologic tissue derived small diameter vascular grafts; while relatively effective on the short term, these scaffolds are affected by a number of issues such as: inadequate mechanics or mechanical mismatch, re-stenosis due to intimal hyperplasia or thrombosis. This study aims to introduce a novel processing technique for small-diameter tissue-engineered vascular graft (TEVG) mimicking the three-layer native vessel structure and mechanics. The current prototype combines the synthetic and biologic graft approach with a three-layer structure of anatomically distinct components designed to duplicate native tissue heterogeneity. The three graft layers are processed with electrosp...

JAMA Ophthalmology, 2020

; for the ABCA4 Disease Consortium Study Group IMPORTANCE The mechanisms behind the phenotypic va... more ; for the ABCA4 Disease Consortium Study Group IMPORTANCE The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management. OBJECTIVE To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1. DESIGN, SETTING, AND PARTICIPANTS Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020. MAIN OUTCOMES AND MEASURES Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed. RESULTS A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P = .02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P = .005). CONCLUSIONS AND RELEVANCE This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.

World Journal of Surgical Oncology, 2011

The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while ... more The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC) in MEN1 patients has been reported between 2.6 and 6%. In the literature data only unilateral development of ACCs in MEN1 patients has been reported. We report a 31 years-old female MEN1-patient, in whom hyperplasia of the parathyroid glands, prolactinoma, non functioning pancreatic endocrine carcinoma and functioning bilateral adrenal carcinomas were diagnosed. Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V) in exon 2 of MEN1 gene, was detected. The association of exon 2 mutation of the MEN1 gene with bilateral adrenal carcinomas in MEN1 syndrome, should be further investigated.

American Journal of Ophthalmology Case Reports, 2022

Purpose To present a case of two siblings with optic atrophy associated with Wolfram Syndrome. Ob... more Purpose To present a case of two siblings with optic atrophy associated with Wolfram Syndrome. Observations Two young adult siblings presented with serious bilateral loss of vision and dyschromatopsia established in early adolescence. They were referred with a presumed diagnosis of Leber's Hereditary Optic Neuropathy. At baseline, visual acuity was 20/400 in the right eye and 20/200 in the left eye in patient A and 20/200 in both eyes in patient B, color perception tested with pseudo-isochromatic plates was 0/17 in each eye, optic discs were pale, visual field testing revealed diffuse scotomas bilaterally while electrophysiology showed delayed prominent positive deflection (P100) values in both patients. Personal history revealed Type 1 diabetes mellitus since early childhood. Patients were lost to follow-up and presented 4 years later with significant VA decrease (<20/400) and suspected hearing loss. At that point, genetic testing revealed a pathogenic variation in the WFS1 gene thus confirming the diagnosis of Wolfram syndrome. Treatment with idebenone was proposed, to which only one of the siblings agreed. The other patient remained under observation, as no known treatment for optic atrophy in Wolfram syndrome exists to date. Conclusions and importance Wolfram syndrome is a rare neurodegenerative genetic disease associated with diabetes mellitus, optic atrophy and deafness. Careful and detailed medical and family history led to appropriate testing that confirmed the diagnosis of Wolfram syndrome. To this day, there is no definite treatment for this disease, but the experimental use of idebenone has been suggested to improve visual function. Genetic testing of family members and offspring of patients is strongly recommended.

Blood

Interstitial deletion or loss of chromosome 5 [del (5q) or -5], is a frequent finding in myeloid ... more Interstitial deletion or loss of chromosome 5 [del (5q) or -5], is a frequent finding in myeloid leukemias and myelodysplasias (MDS) including a small subset of chronic myelogenous leukemia patients. Our group has focused on the 5q23–31 region encompassing the IL3-GMCSF and TCF-1 genes. To this end, we have initiated a systematic analysis of this subregion by generating a physical and transcript map employing a series of molecular and bioinformatics approaches. In our systematic search for genes involved in leukemogenesis, we have identified in the present study a novel gene and two novel splice variants of the chondroitin synthase 3 gene. The novel gene exhibits significant alternative splicing, generating at least seven splice variants encoding five putative proline-rich protein isoforms, sharing the N-terminal and central regions, while varying at the C-terminus. Interestingly, the novel protein contains several copies of the PXXP motif and one copy of the PPLP motif, a feature o...

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American journal of ophthalmology case reports, 2018

To investigate the association between novel mutations to bilateral anterior pyramidal congenital... more To investigate the association between novel mutations to bilateral anterior pyramidal congenital cataracts (APyC), complete and intact irides, and nystagmus. This is a retrospective observational case series in a multi-center setting with genetic testing. Three female patients were diagnosed with bilateral APyC, intact irides and nystagmus. Genetic testing identified the three patients had novel missense mutations in - c.128C > T; p.Ser43Phe (S43F), c. 197T > A; p.Ile66Asn (I66N) and c.781C > G; p.Arg261Gly (R261G). This study demonstrates a novel phenotype of bilateral APyC, intact irides, and nystagmus in whom genetic testing for identified novel missense mutations (S43F, I66N, R261G) in highly conserved DNA-binding domains. Implications of understanding why the iris is present in these cases is discussed.

EBioMedicine, Jan 24, 2018

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh... more Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with L...

Amer J Hum Genet, 1994

Genetic linkage studies have established a region on the short arm of the human X chromosome (Xp1... more Genetic linkage studies have established a region on the short arm of the human X chromosome (Xp11.22-Xp11.3) to be implicated in several inherited opthalmic diseases. Aland Island eye disease (AIED), congenital stationary night blindness 1 (CSNB1), X-linked progressive cone dystrophy and one form of retinitis pigmentosa (RP2) all map to the interval. A lack of multiple informative recombinants in RP2

Molecular Vision, 2014

Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy characterized by bilater... more Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy characterized by bilateral and symmetric optic nerve pallor associated with insidious decrease in visual acuity with onset usually in early childhood. ADOA (estimated prevalence between 1/50,000 worldwide [1] and 1/10,000 in Denmark [2-4]) and Leber hereditary optic neuropathy (LHON; prevalence between 1/30,000 and 1/50,000 [5,6]) are the most common forms of inherited optic neuropathies. Even though evidence of dominantly inherited optic neuropathy was presented before 1900, only after the description of 19 families by the ophthalmologist Kjer was ADOA (also called Kjer type optic atrophy) recognized. The diagnostic criteria established in several studies during the past few decades [3,7] include slowly progressive bilateral visual impairment, dyschromatopsia, loss of sensitivity in the central visual field, and temporal optic disc atrophy beginning before the age of 10 years [8]. The precise age of onset is rarely established; most patients are diagnosed when they enter school or only incidentally following the examination of other affected family members [9].