Werner Syndrome Research Articles

CLINICAL CASE – SCLEREDEMA ADULTORUM

Scleredema of Buschke is a rare dermal disease of unknown etiology which is characterized by a dense diffuse swelling of the derm and subcutaneous adipose tissue. It characterized by induration of the skin which includes a non-pitting hardening of the skin around the neck, shoulders, and trunk sometimes the face. Three basic forms are distinguished: classical, idiopathic, diabetic or metabolic. The histopathological features of scleredema are characterized by sharply thickened derma, edema and structural impairment of collagenous fascicles metachromasia appears in the foci of the damage as a result of accumulation of glycosaminoglycans. Differential diagnostics was carried out at the other diseases similar to scleredema such as systemic scleroderma, eosinophilic fasciitis, porphyria cutanea tarda hereditaria, porphyria cutanea scleroderma-like form, Werner's syndrome, scleromyxedema, amyloidosis. Several treatments are suggested in the literature. The present case record describes scleredema adultorum Buschke in a 52- years-old male with stiffness and density of the skin of trunk. He had suffered from diabetes mellitus type-1 for more than 30 years. The patient was treated with antibiotics, corticosteroids, polyenzyme agent, hepatoprotector, cytoflavin, polyvitamins. There was improvement with slightly decrease infiltration in foci lesions, skin color in the area of rash brightened. Skin diseases are common in diabetes mellitus. This clinical case will enable to expand knowledge of general practitioners about the rare dermal disease – Buschke's scleredema giving the possibility to reveal such patients at early stages of the disease in proper time.

Targeted inhibition of WRN helicase by external guide sequence and RNase P RNA

Human WRN, a RecQ helicase encoded by the Werner syndrome gene, is implicated in genome maintenance, including replication, recombination, excision repair and DNA damage response. These genetic processes and expression of WRN are concomitantly upregulated in many types of cancers. Therefore, targeted destruction of this helicase could be useful for elimination of cancer cells. Here, we provide a proof of concept for applying the external guide sequence (EGS) approach in directing an RNase P RNA to efficiently cleave the WRN mRNA in cultured human cell lines, thus abolishing translation and activity of this distinctive 3′–5′ DNA helicase–nuclease. Remarkably, EGS-directed knockdown of WRN leads to severe inhibition of cell viability. Hence, further assessment of this targeting system could be beneficial for selective cancer therapies, particularly in the light of the recent improvements introduced into EGSs.

Inflammageing assessed by MMP9 in normal Japanese individuals and the patients with Werner syndrome.

Age-associated minor inflammation: inflammageing may explain human ageing mechanism(s). Our previous study reported a significant increase in the serum level of highly sensitive C-reactive protein (hsCRP) with normal ageing and the patients with Werner syndrome (WS). To further study the minor inflammatory condition associated with ageing, another possible ageing biomarker: matrix metalloproteinase-9 (MMP9) was examined in the sera from 217 normal Japanese individuals aged between 1 and 100 years and 41 mutation-proven Japanese WS aged between 32 and 70 years. MMP9 was assayed by ELISA. The serum level of MMP9 was elevated significantly (p < 0.001) with normal ageing from both sexes as hsCRP. In contrast to normal ageing, the serum MMP9 level in WS decreased significantly with calendar age (p < 0.05). The MMP9 level (ng/mL) in WS (147.2 ± 28.5) was not significantly different in comparison with those from age-matched normal adult population aged between 25 and 70 years (109.1 ± 9.4), nor normal elderly population aged between 71 and 100 years (179.9 ± 16.1). Although both normal ageing and WS were associated with minor inflammation, the inflammatory parameters such as serum MMP9 and hsCRP changed differently between normal ageing and WS. The WS-specific chronic inflammation including skin ulcer and diabetes mellitus may contribute the different behavior of both ageing biomarkers from normal ageing.

AN ORPHAN PHENOTYPE OF CARDIOGENITAL LAMINOPATHY — MALOUF SYNDROME

Recent decades significantly increased the spectrum of monogenic diseases associated with mutations in the gene of lamin A/C (LMNA), that codes the proteins group performing important functions in the nucleus. This pathology presents with diverse systemic tissue involvement. Mutations of the gene LMNA are the cause of more than ten different inherited disorders — laminopathies. In clinical practice, there are cardial phenotypes common, i. e. dilation cardiomyopathy (DCMP), skeletal-muscular dystrophies (Emery-Dreifuss dystrophy, inherited and limbleveled) and more rare forms — lipodystrophies, progeroid phenotypes (acromandibular dysplasia, Hutchinson-Gilford progeria, atypical Werner syndrome), Malouf syndrome. Malouf syndrome, known nowadays as cardiogenital syndrome, is rare inborn pathology with DCMP phenotype and ovarial dysgenesis (females) or primary testicular failure (males), with cognitive delay and variety of skeletal abnormalities (usually facial dysmorphism and marfanoid signs). The arcticle presents a clinical case of female patient with primary amenorrhea, hypogonadism, DCMP, cognitive deficiency, hypodeveloped secondary gender signs, body mass deficiency, and facial dysmorphism. Radiation, viral parotitis, autoimmunity and Turner syndrome were ruled out. Signs if bone dysplasia typical for mandibular-acral dysplasia are absent. Relatives of the 1st line are normal. With sequencing method, we searched for mutations in the gene LMNA, but there were no mutations. Results make it to suggest that pathogenetic mechanisms of Malouf syndrome are not only of “lamin” nature but of other genetic causes too. The article also points on the key issues of diagnostics and treatment, presents differential criteria and clinical signs of an orphan disease.

Diagnosis and Management of Hereditary Thyroid Cancer.

Thyroid cancers are largely divided into medullary (MTC) and non-medullary (NMTC) cancers , depending on the cell type of origin. Familial non-medullary thyroid cancer (FNMTC) comprises about 5-15% of NMTC and is a heterogeneous group of diseases, including both non-syndromic and syndromic forms. Non-syndromic FNMTC tends to manifest papillary thyroid carcinoma , usually multifocal and bilateral . Several high-penetrance genes for FNMTC have been identified, but they are often confined to a few or single families, and other susceptibility loci appear to play a small part, conferring only small increments in risk. Familial susceptibility is likely to be due to a combination of genetic and environmental influences. The current focus of research in FNMTC is to characterise the susceptibility genes and their role in carcinogenesis. FNMTC can also occur as a part of multitumour genetic syndromes such as familial adenomatous polyposis , Cowden's disease , Werner's syndrome and Carney complex . These tend to present at an early age and are multicentric and bilateral with distinct pathology. The clinical evaluation of these patients is similar to that for most patients with a thyroid nodule. Medullary thyroid cancer (MTC) arises from the parafollicular cells of the thyroid which release calcitonin. The familial form of MTC accounts for 20-25% of cases and presents as a part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes or as a pure familial MTC (FMTC). They are caused by germline point mutations in the RET oncogene on chromosome 10q11.2. There is a clear genotype-phenotype correlation, and the aggressiveness of FMTC depends on the specific genetic mutation, which should determine the timing of surgery.

The Expression Levels of XLF and Mutant P53 Are Inversely Correlated in Head and Neck Cancer Cells.

XRCC4-like factor (XLF), also known as Cernunnos, is a protein encoded by the human NHEJ1 gene and an important repair factor for DNA double-strand breaks. In this study, we have found that XLF is over-expressed in HPV(+) versus HPV(-) head and neck squamous cell carcinoma (HNSCC) and significantly down-regulated in the HNSCC cell lines expressing high level of mutant p53 protein versus those cell lines harboring wild-type TP53 gene with low p53 protein expression. We have also demonstrated that Werner syndrome protein (WRN), a member of the NHEJ repair pathway, binds to both mutant p53 protein and NHEJ1 gene promoter, and siRNA knockdown of WRN leads to the inhibition of XLF expression in the HNSCC cells. Collectively, these findings suggest that WRN and p53 are involved in the regulation of XLF expression and the activity of WRN might be affected by mutant p53 protein in the HNSCC cells with aberrant TP53 gene mutations, due to the interaction of mutant p53 with WRN. As a result, the expression of XLF in these cancer cells is significantly suppressed. Our study also suggests that XLF is over-expressed in HPV(+) HNSCC with low expression of wild type p53, and might serve as a potential biomarker for HPV(+) HNSCC. Further studies are warranted to investigate the mechanisms underlying the interactive role of WRN and XLF in NHEJ repair pathway.

The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells.

Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580.

Speeding up the clock: The past, present and future of progeria

Progeria is a devastating disorder in which patients exhibit signs of premature aging. The most well-known progeroid syndromes include Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner Syndrome (WS). While HGPS and WS are rare, they often result in severe age-associated complications starting in the early developmental period or after the pubertal growth spurt during adolescence, respectively. In addition, patients with HGPS ultimately die of diseases normally seen in the elderly population, with stroke and myocardial infarction as the leading causes of death. Many WS patients develop similar cardiovascular complications but also have an increased predisposition to developing multiple rare malignancies. These premature aging disorders, as well as animal and cell culture models that recapitulate these diseases, have provided insight into the genetics and cellular pathways that underlie these human conditions and have also uncovered possible mechanisms behind normal aging. Here we discuss the history, the types of progeria, and the various pathophysiological mechanisms that drive these diseases. We also address recent medical advances and treatment modalities for patients with progeria.

Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway.

Faithful and complete genome replication in human cells is essential for preventing the accumulation of cancer-promoting mutations. WRN, the protein defective in Werner syndrome, plays critical roles in preventing replication stress, chromosome instability, and tumorigenesis. Herein, we report that ATR-mediated WRN phosphorylation is needed for DNA replication and repair upon replication stress. A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. ATR-mediated WRN S1141 phosphorylation leads to ubiquitination of WRN, facilitating the reversible interaction of WRN with perturbed replication forks and subsequent degradation of WRN. The dynamic interaction between WRN and DNA is required for the suppression of new origin firing and Rad51-dependent double-stranded DNA break repair. Significantly, ATR-mediated WRN phosphorylation is critical for the suppression of chromosome breakage during replication stress. These findings reveal a unique role for WRN as a modulator of DNA repair, replication, and recombination, and link ATR-WRN signaling to the maintenance of genome stability.

The Caenorhabditis elegans Werner syndrome protein participates in DNA damage checkpoint and DNA repair in response to CPT-induced double-strand breaks

The RecQ helicases play roles in maintenance of genomic stability in species ranging from Escherichia coli to humans and interact with proteins involved in DNA metabolic pathways such as DNA repair, recombination, and replication. Our previous studies found that the Caenorhabditis elegans WRN-1 RecQ protein (a human WRN ortholog) exhibits ATP-dependent 3′–5′ helicase activity and that the WRN-1 helicase is stimulated by RPA-1 on a long forked DNA duplex. However, the role of WRN-1 in response to S-phase associated with DSBs is unclear. We found that WRN-1 is involved in the checkpoint response to DSBs after CPT, inducing cell cycle arrest, is recruited to DSBs by RPA-1 and functions upstream of ATL-1 and ATM-1 for CHK-1 phosphorylation in the S-phase checkpoint. In addition, WRN-1 and RPA-1 recruitments to the DSBs require MRE-11, suggesting that DSB processing controlled by MRE-11 is important for WRN-1 at DSBs. The repair of CPT-induced DSBs is greatly reduced in the absence of WRN-1. These observations suggest that WRN-1 functions downstream of RPA-1 and upstream of CHK-1 in the DSB checkpoint pathway and is also required for the repair of DSB.

Association of the rs1346044 Polymorphism of the Werner Syndrome Gene RECQL2 with Increased Risk and Premature Onset of Breast Cancer.

Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We analyzed the association of two coding single-nucleotide polymorphisms in WRN, Cys1367Arg (rs1346044), and Arg834Cys (rs3087425), with the risk, age at onset, and clinical subclasses of breast cancer in a hospital-based case-control study of an Austrian population of 272 breast cancer patients and 254 controls. Here we report that the rare homozygous CC genotype of rs1346044 was associated with an approximately two-fold elevated breast cancer risk. Moreover, patients with the CC genotype exhibited a significantly increased risk of developing breast cancer under the age of 55 in both recessive and log-additive genetic models. CC patients developed breast cancer at a mean age of 55.2 ± 13.3 years and TT patients at 60.2 ± 14.7 years. Consistently, the risk of breast cancer was increased in pre-menopausal patients in the recessive model. These findings suggest that the CC genotype of WRN rs1346044 may contribute to an increased risk and a premature onset of breast cancer.

RECQL5 has unique strand annealing properties relative to the other human RecQ helicase proteins

The RecQ helicases play important roles in genome maintenance and DNA metabolism (replication, recombination, repair, and transcription). Five different homologs are present in humans, three of which are implicated in accelerated aging genetic disorders: Rothmund Thomson (RECQL4), Werner (WRN), and Bloom (BLM) syndromes. While the DNA helicase activities of the 5 human RecQ helicases have been extensively characterized, much less is known about their DNA double strand annealing activities. Strand annealing is an important integral enzymatic activity in DNA metabolism, including DNA repair. Here, we have characterized the strand annealing activities of all five human RecQ helicase proteins and compared them. Interestingly, the relative strand annealing activities of the five RecQ proteins are not directly (inversely) related to their helicase activities. RECQL5 possesses relatively strong annealing activity on long or small duplexed substrates compared to the other RecQs. Additionally, the strand annealing activity of RECQL5 is not inhibited by the presence of ATP, unlike the other RecQs. We also show that RECQL5 efficiently catalyzes annealing of RNA to DNA in vitro in the presence or absence of ATP, revealing a possible new function for RECQL5. Additionally, we investigate how different known RecQ interacting proteins, RPA, Ku, FEN1 and RAD51, regulate their strand annealing activity. Collectively, we find that the human RecQ proteins possess differential DNA double strand annealing activities and we speculate on their individual roles in DNA repair. This insight is important in view of the many cellular DNA metabolic actions of the RecQ proteins and elucidates their unique functions in the cell.

Microwell arrays reveal cellular heterogeneity during the clonal expansion of transformed human cells.

We developed micromolded microwell arrays to study the proliferation and senescence of single cells. Microwell arrays were designed to be compatible with conventional cell culture protocols to simplify cell loading, cell culture, and imaging. We demonstrated the utility of these arrays by measuring the proliferation and senescence of isogenic cells which expressed or had been depleted of the human Werner syndrome protein. Our results allowed us to reveal cell-to-cell heterogeneity in proliferation in WRN+ and WRN-depleted fibroblasts during clonal growth.

Abstract 12622: The Modeling of Werner Syndrome by Induced Pluripotent Stem Cells

Backgrounds: Werner syndrome (WS) is a rare autosomal recessive disorder characterized by premature onset of several aging-associated diseases, such as atherosclerosis, diabetes, cancer, and early death. The aging phenotypes of WS is resembling to those of normal aging. To uncover the mechanism of aging, we tried to model WS by patient-specific induced pluripotent stem cells (iPSCs). WS is caused by mutations in WRN gene belonging to the RecQ DNA helicase family which plays a role in genomic stability. But some of WS phenotypes are hardly explained by genomic instability. Thus, we aimed to model WS by patient-specific iPSCs to elucidate the mechanisms. Methods and Results: We sampled T lymphocytes from a patient with WS. Then we transduced with Yamanaka factors (OCT4, SOX2, KLF4, and MYC) by sendai virus, and iPSC colonies were derived. We confirmed that WS-iPSCs expressed pluripotent markers, could differentiate into all three germ-layer derived tissues, and retained a normal karyotype. We could culture WS-iPSCs over 2 years with pluripotent status. Then, we differentiated WS-iPSCs into fibroblasts-like cells. The proliferation rate of WS-iPSC-derived fibroblast-like cells (WS-iPSC-fibroblasts) was significantly decreased. WS-iPSC-fibroblasts showed a vulnerability to cellular stress and resulted in increased cell population which is positive for senescence associated β-galactosidase activity and γ-H2AX foci. Singled WS-iPSC-fibroblasts showed excessive blebbing of plasma membrane and increased apoptosis compared with control-iPSC-fibroblasts. To compare global gene expression profiles, we performed microarray analysis in WS-iPSC-fibroblasts and control-iPSC-fibroblasts. Interestingly, WS-iPSC-fibroblasts reproduced the global gene expression pattern of physiological aging. To confirm whether the phenotypes of WS-iPSCs are induced by WRN mutation, we generated isogenic control of WS-iPSC (corrected-WS-iPSC) by homologous recombination using helper-dependent adenovirus vector. Corrected-WS-iPSCs lost the aging-associated phenotypes but showed the phenotypes resembling to control-iPSCs. Conclusion: We modeled aging phenotypes by WS-specific iPSCs. This model would be utilize for uncovering the aging mechanisms.

Impact of vitamin C on the cardiometabolic and inflammatory profiles of mice lacking a functional Werner syndrome protein helicase

Werner syndrome (WS) is a premature aging disorder caused by mutations in a DNA helicase/exonuclease. Mice lacking the helicase domain of this protein exhibit metabolic abnormalities that are reversed by vitamin C. In this study, we used a targeted metabolomic approach to identify serum metabolites significantly altered in young mutant mice treated with or without vitamin C. We also measured several serum inflammatory and cardiometabolic factors. We show that young mutant mice exhibit an increase in serum hydroxyproline and plasminogen activator inhibitor-1 (PAI-1), markers of cardiovascular diseases and inflammation, before they exhibit morphological anomalies in different tissues. We also observed an increase in three very long chain lysophosphatidylcholines underlying peroxisome perturbation. Vitamin C reversed the concentrations of these metabolites and PAI-1 to wild type values. Transcriptomic analyses on the liver of mutant mice revealed a decrease in the expression of genes involved in fatty acid degradation compared to wild type animals. Vitamin C treatment increased the expression of genes involved in glutathione metabolism and the synthesis of unsaturated fatty acids in these mice. These results show that changes at the transcriptomic level concord with the alterations of several serum metabolites in these mice. Finally, we found that a mislocalization of the Wrn mutant protein in the liver endoplasmic reticulum fraction increased oxidative stress in that cellular compartment. Vitamin C reversed this oxidative stress. To conclude, this study provides novel potential predictive cardiometabolic biomarkers in WS that will allow the assessment of the impact of vitamin C on patients with WS.

Relationships between putative G-quadruplex-forming sequences, RecQ helicases, and transcription.

BackgroundPutative G-quadruplex-forming sequences (PQS) have long been implicated in regulation of transcription, though the actual mechanisms are not well understood. One proposed mechanism involves the activity of PQS-specific helicases belonging to the RecQ helicase family. However, patterns of PQS that correlate with transcriptional sensitivity to RecQ helicases are not well studied, and no adequate transcriptional model exists to account for PQS effects.MethodsTo better understand PQS transcriptional effects, we analyze PQS motifs in genes differentially-transcribed in Bloom Syndrome (BS) and Werner Syndrome (WS), two disorders resulting in loss of PQS-interacting RecQ helicases. We also correlate PQS genome-wide with transcription in multiple human cells lines while controlling for epigenetic status. Finally, we perform neural network clustering of PQS motifs to assess whether certain motifs are over-represented in genes sensitive to RecQ helicase loss.ResultsBy analyzing PQS motifs in promoters of genes differentially-transcribed in BS and WS, we demonstrate that abundance of promoter PQS is generally higher in down-regulated genes and lower in up-regulated genes, and show that these effects are position-dependent. To interpret these correlations we determined genome-wide PQS correlations with transcription while controlling for epigenetic status. Our results identify multiple discrete transcription start site-proximal positions where PQS are correlated with either increased or decreased transcription. Finally, we report neural network clustering analysis of PQS motifs demonstrating that genes differentially-expressed in BS and WS are significantly biased in PQS motif composition.ConclusionsOur findings unveil unappreciated detail in the relationship between PQS, RecQ helicases, and transcription. We show that promoter PQS are generally correlated with reduced gene expression, and that this effect is relieved by RecQ helicases. We also show that PQS at certain positions on the downstream sense strand are correlated with increased transcription. We therefore propose a new transcriptional model in which promoter PQS have at least two distinct types of transcriptional regulatory effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0236-4) contains supplementary material, which is available to authorized users.

A case of Werner's syndrome with cardiac syndrome X and heart failure with preserved ejection fraction

We herein report a case of Werner's syndrome (WS) with cardiac syndrome X (CSX) and heart failure with preserved ejection fraction (HFpEF), receiving nicorandil treatment.A 58-year-old woman with chest discomfort on exercise was suspected of having effort-angina pectoris because of broad ST-depression in electrocardiogram of exercise test and reversible defect in the posterior-wall portion of left ventricle in exercise thallium201 myocardial scintigraphy. This patient also exhibited HFpEF, diagnosed by increased ratio of early-transmitral-flow-velocity to tissue-Doppler early-diastolic mitral annular velocity (E/e′) in echocardiography and plasma B-type natriuretic peptide (BNP) levels. However, coronary angiography revealed no organic stenosis in epicardial coronary arteries, and coronary physiological measurements by PressureWire™ (St. Jude Medical, St Paul, MN, USA) demonstrated that coronary flow reserve (CFR) was greatly decreased. Because impaired CFR represents coronary microvascular dysfunction in the absence of obstructive coronary narrowing, we diagnosed CSX, and initiated the administration of nicorandil to improve coronary microcirculation. After three-month-treatment of nicorandil, the patient's symptoms were diminished, and reversible defect in exercise myocardial scintigraphy was improved. Furthermore, both E/e′ and BNP were decreased, indicating the improvement of HFpEF via the restoration of microvascular dysfunction.Thus, nicorandil administration could bring beneficial effects in WS with CSX and HFpEF, accompanied by coronary microcirculation dysfunction.<Learning objective: Contrary to previous case reports regarding Werner's syndrome (WS) with obstructive coronary artery disease (CAD), we herein report a case of WS with cardiac syndrome X (CSX) without obstructive CAD, complicated with heart failure with preserved ejection fraction (HFpEF). Because impaired coronary microcirculation is known to be associated with left ventricular hypertrophy and HFpEF, nicorandil could improve not only CSX but HFpEF via the restoration of coronary microvascular dysfunction.>

Application of platelet-rich plasma and hyperbaric oxygen therapy during oral surgery in a patient with Werner syndrome

Application of platelet-rich plasma and hyperbaric oxygen therapy during oral surgery in a patient with Werner syndrome

The DNA structure and sequence preferences of WRN underlie its function in telomeric recombination events.

Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome. Here we examine WRN's role in telomeric maintenance, by comparing its action on a variety of DNA structures without or with telomeric sequences. Our results show that WRN clearly prefers to act on strand invasion intermediates in a manner that favours strand invasion and exchange. Moreover, WRN unwinding of these recombination structures is further enhanced when the invading strand contains at least three G-rich single-stranded telomeric repeats. These selectivities are most pronounced at NaCl concentrations within the reported intranuclear monovalent cation concentration range, and are partly conferred by WRN's C-terminal region. Importantly, WRN's specificity for the G-rich telomeric sequence within this precise structural context is particularly relevant to telomere metabolism and strongly suggests a physiological role in telomeric recombination processes, including T-loop dynamics.

Early Onset Werner Syndrome

Werner syndrome (WS) is a rare autosomal recessive adultonset progeroid disorder characterized by the early onset of aged-appearance and age-related metabolic disorders caused by homologous mutations at the WRN helicase locus (1). The features of the syndrome were first described as sclerodermalike skin changes, short stature, gray hair and genital hypoplasia (2). Later, other endocrinological manifestations, including osteoporosis and glucose metabolism abnormalities have been shown to be the components of this syndrome. Generally, the first manifestation of the disease is absence of growth spurt (3). The incidence of WS is one per million. It is known that the frequency of this syndrome is higher in Japan as 75% of patients were reported from Japan between 1904 and 2008 (4). Case reports from Turkey are extremely rare (5,6,7,8). Symptoms of premature aging usually first develop in the third decade of life (3). Herein, we present an atypical case of WS with early onset of premature aging-related metabolic disorders. Werner syndrome (WS) is a rare autosomal recessive adult-onset progeroid disorder characterized by the early onset of aged-appearance and age-related metabolic disorders. Symptoms of premature aging usually first develop in the second-third decades of life. We report a 27-year-old female who was admitted to our clinic at the age of eighteen with hyperglycemia. She was diagnosed with diabetes and type 4 dyslipidemia at the age of seven. In her family history, her parents were first cousins and she had three healthy brothers. On her first physical examination; she had bird-like face appearance, global hair loss, beaked nose, short stature and she was overweight. She had global hair loss with gray and thin hair. Hoarseness of voice and hyperkeratosis of skin were observed. She had bilateral cataracts and moderate sensorineural hearing loss. On psychiatric examination, borderline mental retardation was detected. She had severe insulin resistance and hypertriglyceridemia despite levothyroxine, gemfibrozil, omega-3 and intensive insulin treatment. Routine lipid apheresis was performed to lower the triglyceride levels reaching 5256 mg/dL. She also had focal segmental glomerulosclerosis, hepatosteatosis, osteoporosis and epilepsy. Disease was accompanied by several congenital deformities, such as Rathke’s cleft cyst, angiomyolipoma and femoral neck hypoplasia. WS is a rare genetic disorder characterized by multiple endocrine manifestations as well as soft tissue changes. We present a case of early disturbances that were diagnosed before typical clinical signs and symptoms. We propose that WS should be kept in mind when type 2 diabetes and hyperlipidemia are diagnosed early in childhood. Turk Jem 2015; 19: 99-104