Browsing by Author "Pasha, Shanaz S."

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    Mutations in SLC29a3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease
    (Public Library Science, 2010-02) Morgan, Neil V.; Morris, Mark R.; Gleeson, Diane; Straatman-Iwanowska, Anna A.; Davies, Nicholas James; Keenan, Stephen J.; Pasha, Shanaz S.; Rahman, Fatimah; Gentle, Dean C.; Vreeswijk, Maaike P.G.; Devilee, Peter; Knowles, Margaret A.; Ceylaner, Serdar; Trembath, Richard C.; Dalence, Carlos; Kısmet, Erol; Köseoğlu, Vedat; Rossbach, Hans Christoph; Gissen, Paul; Tannahill, David; Mäher, Eamonn Richard; Cangül, Hakan; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.; 8911611600
    The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder.
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    Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism
    (Wiley, 2010-11) Morgan, Neil V.; Forman, Julia R.; Aycan, Zehra; Böber, Ece; Cesur, Yaşar; Kirby, Gail A.; Pasha, Shanaz S.; Çetinkaya, Semra Çağlar; Baş, Veysel Nihat; Demir, Korcan; Yuca, Sevil Arı; Meyer, Esther; Högler, Wolfgang; Timothy Barrett, Timothy; Mäher, Eamonn Richard; Cangül, Hakan; Sağlam, Halil; Yakut, Tahsin; Gülten, Tuna; Tarım, Ömer Faruk; Karkucak, Mutlu; Eren, Erdal; Kendall, Michaela; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Halk Sağlığı Anabilim Dalı.; 0000-0003-0710-5422; 0000-0002-1684-1053; C-7392-2019; AAM-1734-2020; 8911611600; 35612700100; 6602802424; 6505944216; 6701427186; 35388323500; 36113153400; 8062516400
    Objective Nonsyndromic autosomal recessively inherited non-goitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2-5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG. Design Because consanguinity in individuals with a presumptive genetic condition is often an indicator of an autosomal recessive inheritance and allows firmer correlations to be established between genotype and phenotype, we planned to execute our study in consanguineous families. Patients Hundred and thirty-nine children with CHNG phenotype born to consanguineous families. Measurements First, we investigated cases for evidence of linkage to the four known CHNG genes by microsatellite marker analysis. Mutation analysis by direct sequencing was then performed in those cases in whom linkage to the relevant candidate gene could not be excluded. In addition, in silico analysis of the predicted structural effects of TSHR mutations was performed and related to the mutation-specific disease phenotype. Results Homozygous germline TSHR mutations were detected in six families (5%), but no mutations were detected in PAX8, TSHB and NKX2-5. Four of TSHR mutations had not previously been described. Genotype-phenotype correlations were established and found to be related to the predicted structural effects of the mutations. Conclusions Known causative genes account for the development of CHNG only in a minority of cases, and our cohort should provide a powerful resource to identify novel causative genes and to delineate the extent of locus heterogeneity in autosomal recessively inherited CHNG.