Treatment of congenital extrahepatic portosystemic shunts in dogs : a systematic review and meta‐analysis

Background Several options have been proposed for the treatment of congenital extrahepatic portosystemic shunts (cEHPSS) in dogs, but formal comparisons among different treatment options are currently unavailable. A previous evidence-based review (2012) found low quality of evidence for papers assessing the treatment of cEHPSS in dogs. Objectives To assess the quality of evidence available in the treatment of cEHPSS, summarize the current state of knowledge with respect to outcome after cEHPSS management, and compare different treatment techniques. Animals Not used. Methods A bibliographic search was performed without date or language restrictions. Studies were assessed for quality of evidence (study design, study group sizes, subject enrollment quality, and overall risk of bias) and outcome measures reported (perioperative outcome, clinical outcome, and surgical or interventional outcome), all reported with 95% confidence intervals. A network meta-analysis was performed. Results Forty-eight studies were included. Six retrospective studies (grade 4b) compared 2 techniques and 7 were abstracts (grade 5). The quality of evidence was low and risk of bias high. Regarding surgical outcome, statistically significant superiority of ameroid constrictor over thin film band was observed (P = .003). No other comparisons were statistically significant. Conclusions and Clinical Importance The evidence base of choice of treatment of cEHPSS in dogs remains weak despite recent publications on the subject. Ameroid is superior to thin film band in causing EHPSS closure. Blinded randomized studies comparing different treatment modalities, which routinely include postoperative imaging to assess cEHPSS closure and acquired portosystemic shunt development are essential

Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division

The electronic version of this article is the complete one and can be found online at: http://www.pathogeneticsjournal.com/content/3/1/1Background: Aristaless related homeobox (ARX) is a paired-type homeobox gene. ARX function is frequently affected by naturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutations in ARX cause a range of intellectual disability and epilepsy phenotypes with or without additional features including hand dystonia, lissencephaly, autism or dysarthria. Severe malformation phenotypes, such as X-linked lissencephaly with ambiguous genitalia (XLAG), are frequently observed in individuals with protein truncating or missense mutations clustered in the highly conserved paired-type homeodomain. Results: We have identified two novel point mutations in the R379 residue of the ARX homeodomain; c.1135C>A, p.R379S in a patient with infantile spasms and intellectual disability and c.1136G>T, p.R379L in a patient with XLAG. We investigated these and other missense mutations (R332P, R332H, R332C, T333N: associated with XLAG and Proud syndrome) predicted to affect the nuclear localisation sequences (NLS) flanking either end of the ARX homeodomain. The NLS regions are required for correct nuclear import facilitated by Importin 13 (IPO13). We demonstrate that missense mutations in either the N- or C-terminal NLS regions of the homeodomain cause significant disruption to nuclear localisation of the ARX protein in vitro. Surprisingly, none of these mutations abolished the binding of ARX to IPO13. This was confirmed by co-immunoprecipitation and immmuno fluorescence studies. Instead, tagged and endogenous IPO13 remained bound to the mutant ARX proteins, even in the RanGTP rich nuclear environment. We also identify the microtubule protein TUBA1A as a novel interacting protein for ARX and show cells expressing mutant ARX protein accumulate in mitosis, indicating normal cell division may be disrupted. Conclusions: We show that the most likely, common pathogenic mechanism of the missense mutations in NLS regions of the ARX homeodomain is inadequate accumulation and distribution of the ARX transcription factor within the nucleus due to sequestration of ARX with IPO13.Cheryl Shoubridge, May Huey Tan, Tod Fullston, Desiree Cloosterman, David Coman, George McGillivray, Grazia M Mancini, Tjitske Kleefstra and Jozef Géc

Uncovering Enhancer Functions Using the α-Globin Locus

Over the last three decades, studies of the α- and β-globin genes clusters have led to elucidation of the general principles of mammalian gene regulation, such as RNA stability, termination of transcription, and, more importantly, the identification of remote regulatory elements. More recently, detailed studies of α-globin regulation, using both mouse and human loci, allowed the dissection of the sequential order in which transcription factors are recruited to the locus during lineage specification. These studies demonstrated the importance of the remote regulatory elements in the recruitment of RNA polymerase II (PolII) together with their role in the generation of intrachromosomal loops within the locus and the removal of polycomb complexes during differentiation. The multiple roles attributed to remote regulatory elements that have emerged from these studies will be discussed

1024C>T (R342X) is a recurrent RHF6 mutation also found in the original Borjeson-Forssman-Lehmann syndrome family

Karen M Lower, Göran Solders, Marie-Louise Bondeson, John Nelson, Arne Brun, Joanna Crawford, Gunilla Malm, Mats Börjeson, Gillian Turner, Michael Partington and Jozef Géc