Erkan Koparir

Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.

Differential Expression of Hypertension-associated Micrornas in the Plasma of Patients With White Coat Hypertension

AbstractWhite coat hypertension (WCH) is a high cardiovascular risk condition, and a fundamental understanding of the cause and pathophysiology of the disorder is still lacking. Recent studies demonstrated that microRNAs (miRNAs) are involved in hypertension; however, the roles of miRNAs in WCH are not known.The expressions of selected 10 miRNAs were investigated independently in plasma samples from 30 hypertension (HT) patients, 30 WCH patients, and 30 normotensive (NT) subjects.MiR-21, miR-122, miR-637, and let-7e expression levels were significantly upregulated in the HT group compared with the NT groups (P = 0.017, P = 0.022, P = 0.048, and P = 0.013, respectively). MiR-122 and miR-637 expressions were also significantly upregulated in the WCH group compared with the NT group (P = 0.048 and P = 0.039, respectively). MiR-296-5p expression level was significantly downregulated in HT patients and upregulated in the WCH patients compared with the NT group (P = 0.049 and P = 0.039, respectively).Additionally, the ambulatory 24-hour and daytime systolic and diastolic blood pressures were negatively correlated with miR-296-5p. MiR-296 and miR-637 had area under the curve (AUC) values of 0.778 and 0.774, respectively, which demonstrates their sufficiency to distinguish WCH from NT individuals. MiR-296 and miR-637 had AUC values of 0.868 and 0.680, respectively, which shows their potential to distinguish WCH from HT individuals.We report for the first time a plasma miRNA profile for WCH patients and demonstrate a novel link between miRNA and WCH. These findings may reveal crucial insights into the development of WCH.

Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis.

Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of β‐D‐xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism. Hum Mutat 33:1261–1266, 2012.

Poikiloderma with neutropenia: genotype-ethnic origin correlation, expanding phenotype and literature review.

Poikiloderma with neutropenia (PN), is a rare genodermatosis associated with patognomic features of poikiloderma and permanent neutropenia. Three common recurrent mutations of related gene, USB1, were considered to be associated with three different ethnic origins. The most common recurrent mutation, c.531delA, has been detected in seven Caucasian patients in the literature. In this paper, we present review of all patients from the literature and report two additional patients of Turkish ancestry with the diagnosis of PN. The diagnosis of these two PN patients were made clinically and confirmed by molecular analysis which detected the most common recurrent mutation, c.531delA. Genotype‐ethnic origin correlation hypothesis, therefore, has been strengthened with this result. Short stature in PN, is a common finding, which until now has never been treated with growth hormone (GH). One of our patients is the first patient with attempted treatment of short stature via GH administration. Finally, both of our patients had high‐pitched voice and vocal cord nodules which might be considered as additional clinical findings not associated with PN before.

Circumferential skin folds and multiple anomalies: confirmation of a distinct autosomal recessive Michelin tire baby syndrome

Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Department of Pediatrics, Medical School of Bezmi Alem University, Istanbul and Department of Medical Genetics, Medical School of Osmangazi University, Eskisehir, Turkey Correspondence to Hakan Ulucan MD, PhD, Department of Medical Genetics, Cerrahpasa Medical School of Istanbul University, Istanbul 34098, Turkey Tel: + 90 212 414 30 00 x22 996; fax: + 90 212 414 31 84; e-mail: hulucan@istanbul.edu.tr

A novel case of autosomal dominant cutis laxa in a consanguineous family: report and literature review

Autosomal dominant cutis laxa (ADCL, OMIM #123700) is a rare connective tissue disorder characterized by loose, redundant skin folds that may be apparent form birth or appear later in life. Most severely affected areas are the neck, axillar regions, trunk, and groin. Typically, patients present with characteristic facial features including a premature aged appearance, long philtrum, a high forehead, large ears, and a beaked nose. Cardiovascular and pulmonary complications include bicuspid aortic valves, aortic root dilatation, and emphysema. Sporadically, these complications have been documented to cause premature death. Several rare findings including urogenital anomalies and gastroesophageal problems can be also occur. Most patients harbor a frameshift mutation in one of the five last exons of the ELN gene (ADCL1, OMIM #123700), whereas one patient was described to have a tandem duplication in the FBLN5 gene (ADCL2, OMIM #614434). Here, we present a female ADCL patient, from a consanguineous family, with a novel mutation in ELN and review 39 previously reported ADCL patients. All patients have various skin findings, whereas cardiovascular, pulmonary findings, and multiple hernia were present in 61, 28, and 38% of patients, respectively. Strabismus, urogenital anomalies, gastroesophageal problems, and scoliosis may rarely be present. A clear definition of the ADCL syndrome can enable more accurate genetic counseling.

A novel frameshift mutation and infrequent clinical findings in two cases with Dyggve-Melchior-Clausen syndrome.

Dyggve–Melchior–Clausen syndrome (DMC) (MIM #223800) is a rare autosomal-recessive type of skeletal dysplasia accompanied by variable degrees of intellectual disability (ID). It is characterized by progressive spondyloepimetaphyseal dysplasia leading to disproportionate short stature, microcephaly, and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic in this syndrome. The disorder results from mutations in the dymeclin (DYM) mapped to the 18q12–12.1 chromosomal region. Here, we report two cases with DMC: one with disproportionate short stature, developmental delay, and severe ID with a novel frameshift mutation (c.1028_1056del29) leading to a premature stop codon, and the second patient with classical clinical and radiological features of DMC with mild ID and rectal prolapse, which is very rare. The clinical diagnosis was confirmed with molecular analysis of DYM with a known mutation at c.580C>T (p.R194X). The parents and sibling of the second patient were heterozygous carriers with mild skeletal changes and short stature.

A rare case of split hand/foot malformation with sensorineural hearing loss and Mondini dysplasia.

Manuscript Number: CD-D-12-00025R1 Full Title: A rare case of split hand/foot malformation with sensorineural hearing loss and Mondini dysplasia Article Type: Short Case Report