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nucleoside transport

2010-02-09T08:33:17Z

Plasma membrane transport of nucleosides is mediated by equilibrative and concentrative nucleoside transporters, which may have specificity for purines or pyrimidines.

Nucleoside transport in mammalian cells is performed by two types of transporters: SLC28s and SLC29s.

The SLC28s family is responsible for active, sodium-dependent nucleoside transport mainly in specialised cells. In contrast the SLC29s protein family (also known as equilibrative nucleoside transporters) are passive transporters and have a wide tissue distribution.

While hENT4 functions as an organic cation transporter with minimal interaction with nucleosides or nucleoside analogues, hENT1, hENT2 and hENT3 have been implicated in nucleoside transport and hENT3 has been reported to be a broad selectivity, low affinity nucleoside transporter that can transport adenine.

hENT3 was also reported to be a pH-dependent intracellular transporter with partial localization to late endosomes/lysosomes (the hENT1, 2 and 4 localise to the plasma membrane) and to contain a (DE)XXXL(LI) endosomal/lysosomal targeting motif.

However, it was reported that endogenous hENT3 mainly localises to the mitochondria and is predominantly a mitochondrial transporter.

Although germline mutations in genes encoding the mitochondrial enzymes succinate dehydrogenase and fumarate hydratase are associated with neoplasia, these disorders do not show phenotypic overlap with FHC/fRDD.

hENT3 has a similar broad permeant selectivity for nucleosides and nucleobases and the availability of a cytoplasmic pool of nucleosides is a key requirement for several cellular processes including the nucleoside salvage pathway and the generation of ATP/GTP for energy metabolism and signal transduction pathways.

In view of two early onset cancers in a proband with FHC we wondered whether SLC29A3 might predispose to neoplasia (e.g. by altering adenosine metabolism as extracellular adenosine has been reported to induce apoptosis and proliferation in gastric, leukaemia and hepatic cancer cell lines).

Ectopic expression of SLC29A3 suppressed cell growth in vitro but did not find conclusive evidence of SLC29A3 inactivation in breast or bladder cancers.

Further clinical studies are required to determine whether the frequency of neoplasia in SLC29A3 spectrum disorder is increased or whether the findings in the FHC family are coincidental.

Knockdown of the Drosophila orthologue of SLC29A3 (dENT1) results in a variety of phenotypes ranging from lethality in pupal and pharate adult stages (with complete knockdown) or adult flies with abnormal sensory bristle development (mild knockdown).

The latter phenotype has been linked to abnormalities of insulin signalling pathway, and, in contrast to the growth suppressive effects of hENT3 in human cell line, dENT1 appeared to be a positive promoter of cell size or number.

The identification of genes for rare familial syndromes can provide insights into the molecular pathogenesis of more common disorders. Hence the analysis of the SLC29A3 pathway in sporadic Rosai-Dorfman disease, will be of interest.

Members

SLC5s	SLC5A1
SLC28s	SLC28A1	SLC28A2
SLC29s		SLC29A1	SLC29A2	SLC29A3

familial histiocytoses

2010-02-09T08:25:19Z

Familial forms of histiocytosis are rare.

FHLH can be caused by mutations in the perforin genes (PRF1 and PRF2), MUNC 13-4 and syntaxin-11.

Faisalabad histiocytosis (MIM.602782) was first described as a novel autosomal recessive form of histiocytosis in a highly consanguineous family originating from Pakistan.

SLC29A3

2010-02-09T08:17:40Z

solute carrier family 29 (nucleoside transporters), member 3; ENT3, FLJ11160

Nucleoside transporters, such as SLC29A3, mediate uptake of precursors for nucleotide synthesis by salvage pathways. They are also required for uptake of hydrophilic anticancer and antiviral nucleoside drugs.

PAthology

Germline mutations in H syndrome (MIM.612391)

pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome

SLC29A3 cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease (Plos Genetics)

References

Mutations in the SLC29A3 gene are not a common cause of isolated autoantibody negative type 1 diabetes. Edghill EL, Hameed S, Verge CF, Rubio-Cabezas O, Argente J, Sumnik Z, Dusatkova P, Cliffe ST, Hennekam RC, Buckley MF, Hussain K, Ellard S, Attersley AT. JOP. 2009 Jul 6;10(4):457-8. PMID: 19581757

SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway. Cliffe ST, Kramer JM, Hussain K, Robben JH, de Jong EK, de Brouwer AP, Nibbeling E, Kamsteeg EJ, Wong M, Prendiville J, James C, Padidela R, Becknell C, van Bokhoven H, Deen PM, Hennekam RC, Lindeman R, Schenck A, Roscioli T, Buckley MF. Hum Mol Genet. 2009 Jun 15;18(12):2257-65. PMID: 19336477

CC2D2A

2010-02-07T09:57:13Z

Pathology

CC2D2A mutations in Meckel syndrome (MKS) and Joubert syndrome.

References

CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. Mougou-Zerelli S, Thomas S, Szenker E, Audollent S, Elkhartoufi N, Babarit C, Romano S, Salomon R, Amiel J, Esculpavit C, Gonzales M, Escudier E, Leheup B, Loget P, Odent S, Roume J, Gérard M, Delezoide AL, Khung S, Patrier S, Cordier MP, Bouvier R, Martinovic J, Gubler MC, Boddaert N, Munnich A, Encha-Razavi F, Valente EM, Saad A, Saunier S, Vekemans M, Attié-Bitach T. Hum Mutat. 2009 Nov;30(11):1574-82.PMID: #19777577#

FGFR3-related chondrodysplasias

2010-02-07T09:54:27Z

References

New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling. Schibler L, Gibbs L, Benoist-Lasselin C, Decraene C, Martinovic J, Loget P, Delezoide AL, Gonzales M, Munnich A, Jais JP, Legeai-Mallet L. PLoS One. 2009 Oct 29;4(10):e7633.PMID: #19898608#

2p14-p16 duplication

2010-02-07T09:36:10Z

References

Abnormal muscle development of the diaphragm in a fetus with 2p14-p16 duplication. Guilherme R, Guimiot F, Tabet AC, Khung-Savatovsky S, Gauthier E, Nouchy M, Benzacken B, Verloes A, Oury JF, Delezoide AL, Aboura A. Am J Med Genet A. 2009 Dec;149A(12):2892-7. No abstract available. PMID: #19938079#

interstitial lung disease in patients in ataxia-telangiectasia.

2010-02-04T13:56:02Z

Ataxia-telangiectasia (A-T) is an autosomal-recessive multiorgan disease characterized by progressive neurologic deterioration in which the most common causes of death are diseases of the respiratory system and cancers.

Recognition of interstitial lung disease in patients with A-T and its early treatment could reduce or eliminate pulmonary disease as a leading cause of death for these patients. (#15789441#)

References

Interstitial lung disease in patients with ataxia-telangiectasia. Schroeder SA, Swift M, Sandoval C, Langston C. Pediatr Pulmonol. 2005 Jun;39(6):537-43. PMID: #15789441#

pulmonary interstitial emphysema

2010-02-04T13:32:44Z

Pulmonary interstitial emphysema (PIE) is a form of air block most frequently seen in ventilated preterm infants with severe lung disease; it is rarely reported in spontaneously breathing term infants.

References

Spontaneous pulmonary interstitial emphysema in a term unventilated infant. Freysdottir D, Olutoye O, Langston C, Fernandes CJ, Tatevian N. Pediatr Pulmonol. 2006 Apr;41(4):374-8. PMID: #16447182#

diffuse lung disease in infancy

2010-02-04T13:00:13Z

Thoracoscopic and open lung biopsies are being performed with increasing frequency in neonates and infants and are an important component of the diagnostic evaluation of respiratory compromise in these very young children.

Diffuse lung disease in infancy includes a wide spectrum of developmental, genetic, inflammatory, infectious, and reactive disorders.

The majority of the entities diagnosed in infancy (68%) in this retrospective lung biopsy series are seen almost exclusively in this age group and not in older children and adults.

These include primary disorders of pulmonary and pulmonary vascular development, secondary disorders affecting prenatal and/or postnatal lung growth, genetic disorders of surfactant function, pulmonary interstitial glycogenosis, and neuroendocrine cell hyperplasia of infancy.

Although the diagnostic approach to infant lung biopsies is guided primarily by the clinical history and imaging findings, all cases require careful assessment of alveolar growth, vascular architecture, interstitial cellularity, and histologic patterns associated with genetic abnormalities of surfactant metabolism.

Recognition of one or more of these processes assists not only in treatment planning but also in further diagnostic evaluation and prognostication and may have implications for subsequent siblings and other family members.

A classification system have been developed by a North American multicenter multidisciplinary group to lung biopsies seen at our institution and have used this material to describe and illustrate the spectrum of diffuse lung disease in infancy. (#19323600#)

Considerable confusion exists regarding nomenclature, classification, and management of pediatric diffuse lung diseases due to the relative rarity and differences in the spectrum of disease between adults and young children.

Disorders more prevalent in infancy, including primary developmental and lung growth abnormalities, neuroendocrine cell hyperplasia of infancy, and surfactant-dysfunction disorders, constituted the majority of cases (60%).

Lung growth disorders are often unsuspected clinically and under-recognized histologically.

Cases with known surfactant mutations have characteristic pathologic features.

References

Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Langston C, Dishop MK. Pediatr Dev Pathol. 2009 Nov-Dec;12(6):421-37. PMID: #19323600#

Diffuse lung disease in young children: application of a novel classification scheme. Deutsch GH, Young LR, Deterding RR, Fan LL, Dell SD, Bean JA, Brody AS, Nogee LM, Trapnell BC, Langston C; Pathology Cooperative Group, Albright EA, Askin FB, Baker P, Chou PM, Cool CM, Coventry SC, Cutz E, Davis MM, Dishop MK, Galambos C, Patterson K, Travis WD, Wert SE, White FV; ChILD Research Co-operative. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1120-8. PMID: #17885266# (Free)

A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the chILD pathology co-operative group. Langston C, Patterson K, Dishop MK; chILD Pathology Co-operative Group:, Askin F, Baker P, Chou P, Cool C, Coventry S, Cutz E, Davis M, Deutsch G, Galambos C, Pugh J, Wert S, White F. Pediatr Dev Pathol. 2006 May-Jun;9(3):173-80. PMID: #16944976#

mobid loci identified by CGHarray

2010-02-04T12:57:22Z

References

Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, Ou Z, Wiszniewska J, Driscoll DJ, Maisenbacher MK, Bolivar J, Bauer M, Zackai EH, McDonald-McGinn D, Nowaczyk MM, Murray M, Hustead V, Mascotti K, Schultz R, Hallam L, McRae D, Nicholson AG, Newbury R, Durham-O'Donnell J, Knight G, Kini U, Shaikh TH, Martin V, Tyreman M, Simonic I, Willatt L, Paterson J, Mehta S, Rajan D, Fitzgerald T, Gribble S, Prigmore E, Patel A, Shaffer LG, Carter NP, Cheung SW, Langston C, Shaw-Smith C. Am J Hum Genet. 2009 Jun;84(6):780-91. PMID: #19500772#