A Novel Non-Sense Mutation in the SLC2A10 Gene of an Arterial Tortuosity Syndrome Patient of Kurdish Origin

Eur J Pediatr DOI 10.1007/s00431-008-0839-2

SHORT REPORT

A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin

Syed H. E. Zaidi & Sascha Meyer & Vanya D. Peltekova & Angelika Lindinger & Ahmad S. Teebi & Muhammad Faiyaz-Ul-Haque

Received: 30 June 2008 /Accepted: 8 September 2008 # Springer-Verlag 2008

Abstract Arterial tortuosity syndrome (ATS) is a rare and characteristic facial features may carry mutations in the autosomal recessive disorder in which patients display SLC2A10 gene. tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This Keywords Arterial tortuosity syndrome . SLC2A10 gene . syndrome is caused by mutations in the SLC2A10 gene. Non-sense mutation . Hernia In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue Arterial tortuosity syndrome (ATS, OMIM #208050) is a rare features, displays stomach displacement within the thorax autosomal recessive disorder in which patients display and bilateral hip dislocation. Clinical details of this patient tortuosity, aneurysms, and stenosis of the greater and have been reported previously. Sequencing of the SLC2A10 systemic arteries [1, 2, 4, 5, 7, 8, 10, 12–16, 18, 20, 21]. gene identified a novel homozygous non-sense c.756C>A In addition, patients often display hypertextensible skin, mutation in this patient’s DNA. This mutation in the hypermobility of small joints, micrognathia, elongated faces, SLC2A10 gene replaces a cysteine encoding codon with a saggy cheeks, and other connective tissue features. Occa- stop signal. This is believed to cause a premature truncation sionally, ATS patients also display inguinal and diaphrag- of GLUT10 protein in this patient. We conclude that matic hernias, elongation of intestine, arachnodactyly, joint patients of Kurdish origin who display arterial tortuosity contractures, hypotonia, and macrocephaly. Skin hyper- associated with skin hyperextensibility, joint hypermobility, extensibility and joint hypermobility are also cardinal

S. H. E. Zaidi (*) A. S. Teebi Division of Cardiology, Department of Medicine, Section of Clinical Genetics & Dysmorphology, University Health Network & University of Toronto, Hospital for Sick Children, 101 College Street, TMDT East Tower, Room 3-910, Toronto, Ontario, Canada Toronto, Ontario M5G 1L7, Canada e-mail: [email protected] : M. Faiyaz-Ul-Haque S. Meyer A. Lindinger Program in Genetics and Genomic Biology, Universitaetsklinikum des Saarlandes, Kirrberger Strasse, Hospital for Sick Children, Homburg, Germany Toronto, Ontario, Canada

V. D. Peltekova Hospital for Sick Children, Toronto, Ontario, Canada M. Faiyaz-Ul-Haque Department of Pathology & Laboratory Medicine, A. S. Teebi King Faisal Specialist Hospital & Research Centre, Department of Pediatrics, Hamad Medical Corporation, and Department of Genetics, College of Medicine, Weill Cornell Medical College in Qatar, Alfaisal University, Doha, Qatar Riyadh, Saudi Arabia Eur J Pediatr

Fig. 1 Phenotype of the ATS patient. A Patient exhibits an A B elongated face, micrognathia, long philtrum, sagging cheeks, down-slanting palpebral fissures, beaked nose, and low set ears (reproduced from [21] with permission from Wiley-Black- well Publisher). B Chest X-ray after contrast media administra- tion reveals displacement of the stomach in the thorax. C Ra- diograph showing bilateral hip dislocation C

features of Ehlers-Danlos syndrome (EDS) patients [6]. In associated with EDS [1, 19]. Compared to EDS, ATS addition, EDS patients also exhibit dystrophic scarring, easy patients have distinct facial features which manifest as bruising, and connective tissue fragility. These abnormalities elongated faces, micrognathia, small mouth, high arch are not found in ATS patients. In some reports, ATS patients palate, low set ears, long philtrum, beaked nose, down have been described as having arterial tortuosity phenotype slanting palpebral fissures, long ears, and sagging cheeks [1, 2, 7, 8, 18, 20, 21]. While micrognathia, small mouth, and A sagging cheeks have been described in some types of EDS, C G TTTTTGGGCCCCCT A A G elongated face is a unique feature of ATS patients (Fig. 1A). While skin hyperextensibility, joint hypermobility, and some Affected other phenotypic features are shared by EDS and ATS patients, generalized tortuosity of the arterial bed distin- guishes ATS from various types of EDS. For several EDS forms, mutations have been identified COL5A1 COL5A2/COL1A1 C G TTTTTGGGCCCCCT A A G in the following genes: / (EDS- C type 1, OMIM 130000); COL5A1/COL5A2 (EDS-type II, OMIM 130010); COL3A1 & TNXB (EDS-type III, OMIM COL3A1 PLOD Carrier 130020); (EDS-type IV, OMIM 130050); (EDS-type VI, OMIM 225400); COL1A1/COL1A2 (EDS- type VIIA/B, OMIM 130060); ADAMTS2 (EDS-type VIIC, OMIM 225410); B4GALT7 (EDS-progeroid form II, C G TTTTTGGGCCCCCT C A G

R Fig. 2 Identification of a nonsense mutation in the SLC2A10 gene. A Normal Sequence chromatogram of the affected child shows a novel c.756C>A homozygous mutation (upper panel) in the SLC2A10 gene. A carrier parent is heterozygous for this mutation (middle panel). The lower panel shows the sequence of an unaffected non-carrier individual from the family. B Schematic representation of the B GLUT10 protein encoded by the SLC2A10 gene. The 12 transmem- p.C252X brane domains are depicted with filled boxes. The intracellular or 1 541 extracellular domains are represented by open boxes. The location of the p.C252X truncation in the 7th transmembrane domain is identified Eur J Pediatr

OMIM 130070); and COL1A2 (EDS-cardiac valvular form, shown to result in complete lack of GLUT10 expression OMIM 225320). EDS-platelet dysfunction form (OMIM and near-absence of GLUT10 mRNA in smooth muscle 225310) and EDS-like (OMIM 606408) are caused by cells and fibroblasts of ATS patients with premature stop deficiencies of fibronectin and tenascin-X, respectively. codon mutations [9]. It is likely that GLUT10 expression in Molecular causes for Beasly-Cohen type (OMIM 608763), the ATS patient of this study is also absent. This was not EDS-type V (OMIM 305200), and EDS type-unspecified confirmed due to unavailability of the patient. (OMIM 130090) are unknown. Homozygosity mapping of The SLC2A10 gene is expressed during development as the ATS locus to chromosome 20q13 [8, 13] with subsequent well as in adult life. Its mRNA expression has been recorded identification of mutations in the SLC2A10 gene at this locus in a variety of tissues, which include connective tissue, [7, 9, 12, 13] confirmed that ATS is an entirely distinct entity oesophagus, heart, intestine, lung, liver, skin, soft tissue, from EDS. The exact mechanism by which mutations in the stomach, trachea, and vascular tissue (UniGene Hs.305971) SLC2A10 gene produce ATS is not known. [11, 17]. It is important to note that in addition to the We have previously reported a 14-week-old ATS girl of vascular tortuosity, ATS patients display abnormal connec- Kurdish origin with arterial tortuosity and associated tive tissue features, such as loose skin, joint hypermobility, connective tissue features [21]. Microsatellite typing of this and congenital anomalies of the trachea, lung, digestive tract, patient identified homozygosity of the markers for ATS heart, and other tissues in which SLC2A10 expression has locus at chromosome 20q13 [21]. The clinical details of this been reported [1, 7–9, 12–16, 18–21]. An association of ATS ATS patient have previously been reported [21]. Angio- with stroke has also been described [7]. The patient in our graphic examination of the complete vascular tree revealed study also displayed connective tissue abnormalities of lengthening and tortuosity of the aorta, carotid arteries, several organs in addition to the tortuosity of aorta, carotid, subclavian arteries, brachiocephalic artery, pulmonary pulmonary, mesenteric, and renal arteries. It is of note that arteries, mesenteric arteries, renal arteries, and internal and sequence variants in or near the SLC2A10 gene were not external iliac arteries. Aortic root dilatation and stenosis of associated with type 2 diabetes mellitus in Caucasian pulmonary arteries were not present in this patient. Americans, suggesting that GLUT10 is unlikely to contribute Echocardiogram showed normal atria and ventricles. In to this disease in this population [3]. Since ATS patients this study, we describe two additional abnormalities in this survive and possess milder anomalies compared to what is child. These include displacement of stomach (sliding expected for a widely expressed gene, this suggests that hernia) within the thoracic cage and evidence of bilateral GLUT10 is not vital for foetal growth and development to hip dislocation (Fig. 1B,C). In ATS families, stomach adulthood. displacement in the thorax was only reported in a 34-week- It is possible that novel or recurrent mutations in the old fetus upon ultrasound examination [20]. This child was SLC2A10 gene are more frequent in individuals with later identified as carrying a p.Trp170X mutation in the connective tissue abnormalities and stroke who have not SLC2A10 gene [9]. So far there is only a single report of been examined for arterial tortuosity. This study identified a hip dislocation in a 4-year-old ATS patient from Saudi novel missense mutation in the SLC2A10 gene of a patient Arabia [2]. Although rare in ATS, both of these abnor- of distinct ethnic origin. This justifies testing of patients of malities were concurrently present in the affected child Kurdish origin, in which cardiovascular manifestations are described in this article. associated with loose skin, joint laxity, elongated faces, and DNA was isolated from blood of the affected child, other connective tissue phenotypes, for this recurrent or parents, and unaffected siblings. The ATS candidate gene, novel mutation in the SLC2A10 gene. SLC2A10, was sequenced using primers as described elsewhere [9]. A novel homozygous nonsense c.756C>A mutation was discovered in the SLC2A10 gene of the References affected child (Fig. 2A). Both unaffected parents were heterozygous carriers of this mutation. The SLC2A10 gene 1. 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