Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein.

Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl syndrome (BBS), a syndrome caused by defects in cilia transport and function, as well as McKusick-Kaufman syndrome, a genetic disorder characterized by congenital heart defects. Congenital heart defects are rare in BBS, and McKusick-Kaufman syndrome patients do not develop retinitis pigmentosa. Therefore, the McKusick-Kaufman syndrome allele may highlight cellular functions of BBS6 distinct from the presently understood functions in the cilia. In support, we find that the McKusick-Kaufman syndrome disease-associated allele, BBS6H84Y; A242S, maintains cilia function. We demonstrate that BBS6 is actively transported between the cytoplasm and nucleus, and that BBS6H84Y; A242S, is defective in this transport. We developed a transgenic zebrafish with inducible bbs6 to identify novel binding partners of BBS6, and we find interaction with the SWI/SNF chromatin remodeling protein Smarcc1a (SMARCC1 in humans). We demonstrate that through this interaction, BBS6 modulates the sub-cellular localization of SMARCC1 and find, by transcriptional profiling, similar transcriptional changes following smarcc1a and bbs6 manipulation. Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients.

Translational repression of the McKusick-Kaufman syndrome transcript by unique upstream open reading frames encoding mitochondrial proteins with alternative polyadenylation sites.

BACKGROUND: Upstream open reading frames (uORFs) are commonly found in the 5'-untranslated region (UTR) of many genes and function in translational control. However, little is known about the existence of the proteins encoded by uORFs, and the role of the proteins except translational control. There was no report about uORFs of the McKusick-Kaufman syndrome (MKKS) gene that causes a genetic disorder. METHODS: Northern blotting, 3'-RACE, and bioinformatics were used for determining the length of transcripts and their 3' ends. Luciferase assay and in vitro translation were used for evaluation of translational regulatory activity of uORFs. Immunoblotting and immunocytochemical analyses were used for detection of uORF-derived protein products and their subcellular localization. RESULTS: The MKKS gene generates two types of transcripts: a canonical long transcript that encodes both uORFs and MKKS, and a short transcript that encodes only uORFs by using alternative polyadenylation sites at the 5'-UTR. The simultaneous disruption of the uORF initiation codons increased the translation of the downstream ORF. Furthermore, both protein products from the two longest uORFs were detected in the mitochondrial membrane fraction of HeLa cells. Database searches indicated that such uORFs with active alternative polyadenylation sites at the 5'-UTR are atypical but surely exist in human transcripts. CONCLUSIONS: Multiple uORFs at the 5'-UTR of the MKKS long transcript function as translational repressor for MKKS. Two uORFs are translated in vivo and imported onto the mitochondrial membrane. GENERAL SIGNIFICANCE: Our findings provide unique insights into production of uORF-derived peptides and functions of uORFs.

BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition.

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal abnormalities, and cognitive impairment for which 15 causative genes have been identified. Here we present the results of a mutational analysis of our multiethnic cohort of 83 families (105 cases); 75.9% of them have their mutations identified including 26 novel changes. Comprehensive phenotyping of these patients demonstrate that the spectrum of clinical features is greater than expected and overlapped with the features of other ciliopathies; specifically Alström and McKusick-Kauffman syndromes.

Late prenatal diagnosis of hydrometrocolpos secondary to a cloacal anomaly by abdominal ultrasonography with complementary magnetic resonance imaging.

OBJECTIVE: Prenatal diagnosis of a cloacal anomaly is difficult. Magnetic resonance imaging (MRI) can assist in the identification of the connection and continuity of a cystic mass to confirm the diagnosis of a cloacal anomaly. CASE REPORTS: In the first case, a fetal abdominal cystic mass was observed at 32 weeks of gestation. Ultrasonography revealed a retrovesical septate hypoechoic mass with bilateral hydronephrosis. MRI demonstrated a midline cystic mass connected to a dilated uterus and a possible fistula between the bladder and vagina. In the second case, a fetal abdominal septate cystic mass was identified using ultrasonography at 34 weeks of gestation. MRI was performed and demonstrated hydrocolpos/hydrometrocolpos originating from a uterine didelphis with left dysgenesis and a possible vesicovaginal fistula. After birth, both newborns underwent immediate surgical intervention with good outcomes. CONCLUSION: MRI facilitated the prenatal diagnosis of cloacal anomalies and allowed additional time for parental counseling and planning of the delivery method with subsequent neonatal intensive care and surgical and urologic consultations.

Vaginal masses: magnetic resonance imaging features with pathologic correlation.

The detection of vaginal lesions has increased with the expanding use of cross-sectional imaging. Magnetic resonance imaging (MRI) - with its high-contrast resolution and multiplanar capabilities - is often useful for characterizing vaginal masses. Vaginal masses can be classified as congenital, inflammatory, cystic (benign), and neoplastic (benign or malignant) in etiology. Recognition of the typical MR imaging features of such lesions is important because it often determines the treatment approach and may obviate surgery. Finally, vaginal MR imaging can be used to evaluate post-treatment changes related to previous surgery and radiation therapy. In this article, we will review pertinent vaginal anatomy, vaginal and pelvic MRI technique, and the MRI features of a variety of vaginal lesions with pathological correlation.

Squamous cell peritonitis associated with hydrometrocolpos in a multimalformed newborn.

We present the case of a 1 day-old newborn with extensive squamous cell peritonitis resulting from vaginal atresia with hydrometrocolpos and squamous cell reflux through the genital system, a combination rarely recognized in the literature. Delivery was preceded by ultrasound diagnosis of oligohydramnios and "large bladder," the latter representing the dilated proximal vagina. Additional findings included paraesophageal hiatus hernia containing squames, urethral atresia, absence of vulva, lung hypoplasia, mild hypoplasia of the corpus callosum, and short umbilical cord with single umbilical artery (SUA). The possible relationship of the SUA with the constellation of infradiaphragmatic malformations is discussed.

Hidrocolpo por ectopia ureteral em hemivagina associado a displasia renal: relato de caso e revisão da literatura / Congenital hydrocolpos due to ectopic ureter in hemivagina associated with renal dysplasia: a case report and review of the literature

Os autores apresentam um caso de displasia renal associada a ectopia ureteral vaginal homolateral, com uretero-hidronefrose contralateral devida a compressão por hidrocolpo causado pela ectopia e por um septo vaginal oblíquo. Os exames de imagem utilizados foram urografia excretora, cistografia, ultra-sonografia, tomografia computadorizada e cintilografia renal com Tc-99m-DMSA. Foi realizada revisão da literatura sobre casos de hidrocolpo associado a malformações urinárias.

The authors report a case of congenital hydrocolpos due to vaginal malformation (vaginal septae) associated with ectopic ureter and renal displasia. Several imaging diagnostic procedures (ultrasonography, nuclear medicine, intravenous urography and computed tomography) were performed. A review of the literature on hydrocolpos and its association with urinary malformations is also presented