Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB

Usher syndrome is recognized as the most frequent cause of hereditary deaf-blindness. Usher syndrome type I (USH1), the most severe form of the disease, is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction, and retinitis pigmentosa of prepubertal onset. This form is genetically heterogeneous and five loci (USH1A-E) have been mapped thusfar. However, only the gene responsible for USH1 B (which accounts for approximately 75% of USH1 cases) has been characterized. It encodes a long-tailed unconventional myosin, myosin VIIA, with a predicted 2215 amino acid sequence. Primers covering the complete myosin VIIA coding sequence as well as the 3' non coding sequence were designed, allowing direct sequence analysis of each of the 48 coding exons and flanking splice sites in seven patients affected by USH1. Four novel mutations were thereby identified. The possibility should now be considered of a sequence-based prenatal diagnosis in some of the families affected by this very severe form of Usher syndrome.      

Cholesterol crystal embolization diagnosed on bladder transurethral resection

Cholesterol crystal embolization (CCE) is a severe systemic disorder caused by vascular migration of cholesterol crystals originating from ulcerative atherosclerotic plaques located in large arteries. We report 2 cases of CCE diagnosed on bladder transurethral resection in 2 men aged 94 and 72 years. Both patients had atherosclerosis disease. One patient had been treated by heparin 1 month before for pulmonary embolism and the other had had a coronary angiography and bypass graft surgery 5 months before for silent myocardial infarction. One patient presented with hematuria and the other with acute renal failure. Cystoscopy showed multiple papillary tumors of the bladder wall. Bladder transurethral resections showed transitional cell carcinoma with cholesterol crystals occluding the lumen of small arterioles in the submucosa. Eight cases of CCE in the bladder wall have been reported in the literature in 3 women and 5 men aged 56 to 79 years. Cholesterol crystal embolization is often discovered in the bladder wall on necropsy specimens. Only 2 cases have been fortuitously discovered on bladder transurethral resection performed for transitional cell carcinoma. Cholesterol crystal embolization in the bladder wall is often a marker of severe disease although the evolution is quite favorable in our patients, still alive 1 and 2 years after diagnosis.     

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

Mutations in GJB2 are the most common cause of congenital nonsyndromic hearing loss. The controversial allele variant M34T has been hypothesized to cause autosomal dominant or recessive nonsyndromic hearing impairment and some in vitro data has been consistent with this hypothesis. In this report, we present the clinical and genotypic study of 11 families (seven familial forms of nonsyndromic sensorineural hearing loss (NSSNHL) and four sporadic cases) in which the M34T GJB2 variant has been identified. The M34T mutation did not segregate with the deafness in six of the seven familial forms of NSSNH. Eight persons with normal audiogram presented a heterozygous M34T variation and five normal hearing individuals were composite heterozygous for M34T and another GJB2 mutation. Four normal hearing individuals with a documented audiogram were M34T/35delG and one was M34T/(GJB6-D13S1830)del. Screening a French control population of 116 subjects we have found an M34T allele frequency of 1.72%. This percentage was not significatively different from the prevalence of the M34T allele in the deaf population, which was 2.12%. All these data suggest that the M34T variant is not clinically significant in human and is a frequent polymorphism in France.     

The filaria Litomosoides galizai in mites; microfilarial distribution in the host and regulation of the transmission

The mites, Bdellonyssus bacoti, are engorged on rodents having 800 to 60,000 microfilarie/10 mm3 blood. Quantitation of L. galizai larval development shows that an additional blood meal improves development and that high microfilaremiae do not result in a proportional increase in the number of infective larvae. The first important stage of transmission regulation occurs during ingestion of microfilariae: the numbers of ingested microfilariae are lower than expected in cases of high microfilaremia. This phenomenon cannot be ascribed to the mite vector that engorges a constant blood meal whatever the level of microfilaremia. Contrarily, one finds that microfilarial density in the small peripheral blood vessels (blood drawn from incision of the dorsal skin) increases less than in large blood vessels (retro-orbital sinus). A similar observation was reported by Dickerson et al. (1989) working with Wuchereria bancrofti. We assume that in both cases, the high microfilaremiae cause the small blood vessles accessible to the vector to become saturated with parasites. Although regulation during engorging is not the sole factor to monitor the infection in B. bacoti (another one operates during larval development of L. galizai), demonstrating its existence seems to us fundamental: it points out the concept that sub-ingestion, as well as over-ingestion, shows the inequalities of microfilarial densities in the host which seem to be dependent on mechanical factors such as the diameter of blood vessles and the size of microfilariae.     

Two large French pedigrees with non syndromic sensorineural deafness and the mitochondrial DNA T7511C mutation: evidence for a modulatory factor

Hearing impairment is the most frequent sensory defect in children, with a genetic basis in about 50% of cases. Several point mutations and deletions in mitochondrial DNA (mtDNA) have been identified in non-syndromic sensorineural hearing loss (NSSNHL). Beside the frequent A1555G mutation, a number of mutations in tRNAs have been reported recently, but their incidence remains unknown. We identified the T7511C mutation in the tRNASer(UCN) gene in two French families with isolated deafness. Maternal transmission was obvious in both. The 15 patients with hearing impairment exhibited a variable disease phenotype in terms of onset, severity, and progression. T7511C was present in all the patients screened. Homoplasmic and heteroplasmic levels were observed and did not correlate with the severity of the disease. T7511C was also present in 12 hearing offspring of the oldest deaf mothers, confirming the existence of modulatory factors. Our data suggest that this mtDNA mutation should be screened for in all cases of familial NSSNHL compatible with maternal transmission.     

Isolation and characterization of liver-derived hepatitis B e antigen

Two subpopulations of hepatitis B e antigen (HBeAg) were isolated from a human liver infected with hepatitis B virus. HBeAg extracted from liver homogenate subsequent to treatment with buffered 3 M NaSCN or 0.5 M MgCl2 banded at the density of 1.13 g/cm3 in CsCl and was polydispersed on gel filtration. In contrast, HBeAg released with phosphate-buffered saline (PBS) was detected mainly at a density of 1.20 g/cm3 in a CsCl gradient and consisted of low molecular weight species on gel chromatography. Polypeptides of 40,000 and 45,000 daltons were found in NaSCN and PBS-released HBeAg preparations, respectively. The results are interpreted as suggestive that liver HBeAg is a dimer of the major core particle polypeptide in different physicochemical forms.     

Arterial vascularization of the human moderator band: an analysis of this structure's role as a collateral circulation route

In the human heart, the moderator band, or trabecula septomarginalis, is a muscle column that courses inferiorly from the right portion of the interventricular septum to the base of the anterior papillary muscle of the right ventricle This muscular structure is crossed by one or more arteries, which come from the anterior interventricular artery and perfuses the anterior papillary muscle of the right ventricle. In order to clarify the arterial supply of this muscle column, we studied 28 adult hearts, free of any signs of coronary disorder. The path of the moderator band artery was followed by means of microdissection, and we studied the source, course, and interconnections made with other arteries. We observed that the source of the moderator band artery lies in the first three anterior septal arteries, most often in the second one. In relation to the short axis of the heart, the artery of the moderator band can either follow a horizontal path to the septal papillary muscle of the right ventricle or an oblique route to the moderator band, depending on the position of its source. In all the hearts studied, the moderator band artery made anastomotic connections at the base of the anterior papillary muscle of the right ventricle with various branches of the right coronary artery, which means that it can play a key role in collateral circulation following obstruction of the epicardium coronary arteries.     

Mariner is defective in myosin VIIA: a zebrafish model for human hereditary deafness

The zebrafish (Danio rerio) possesses two mechanosensory organs believed to be homologous to each other: the inner ear, which is responsible for the senses of audition and equilibrium, and the lateral line organ, which is involved in the detection of water movements. Eight zebrafish circler or auditory/vestibular mutants appear to have defects specific to sensory hair cell function. The circler genes may therefore encode components of the mechanotransduction apparatus and/or be the orthologous counterparts of the genes underlying human hereditary deafness. In this report, we show that the phenotype of the circler mutant, mariner, is due to mutations in the gene encoding Myosin VIIA, an unconventional myosin which is expressed in sensory hair cells and is responsible for various types of hearing disorder in humans, namely Usher 1B syndrome, DFNB2 and DFNA11. Our analysis of the fine structure of hair bundles in the mariner mutants suggests that a missense mutation within the C-terminal FERM domain of the tail of Myosin VIIA has the potential to dissociate the two different functions of the protein in hair bundle integrity and apical endocytosis. Notably, mariner sensory hair cells display morphological and functional defects that are similar to those present in mouse shaker-1 hair cells which are defective in Myosin VIIA. Thus, this study demonstrates the striking conservation of the function of Myosin VIIA throughout vertebrate evolution and establishes mariner as the first fish model for human hereditary deafness.     

Mesothelial cyst of the adrenal gland

We report a case of a mesothelial adrenal cyst which was incidentally discovered in a 38-year old woman. The diagnosis was confirmed by an immunohistochemistry study. Adrenal cysts are rare. They occur more commonly in female patients during the 4th and 5th decades and are usually asymptomatic. Adrenal cysts are divided into four groups : parasitic, epithelial, endothelial cysts and pseudocysts. The management is still discussed : follow-up, surgical resection or fine-needle aspiration.