Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome

Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-L?ken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.     

The effect of 4,5-dichlor-1,3-benzendisulfonamide and of 4,5-dichlor-1,3-benzendisulfonylaniline on the morphogenesis of the otoliths in the chick embryo

Riassunto Inoculando in embrioni di pollo di 4 giorni di sviluppo un inibitore dell'anidrasi carbonica (4, 5-Dicloro-1, 3-Benzendisolfonamide) o un suo derivato inattivo nel quale un atomo di idrogeno dei 2 gruppi SO₂NH₂ è sostituito da radicali fenilici (4, 5-Dicloro-1, 3-Benzendisolfonilanilina), si nota una inibizione selettiva della morfogenesi degli otoliti in presenza di 4, 5-Dicloro-1, 3-Benzendisolfonamide.     

Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.     

Colchicine dissociates the toad (Bufo arenarum) urinary bladder responses to antidiuretic hormone and to serosal hypertonicity

Resumen Los efectos de la ocitocina y la hipertonía serosa sobre la respuesta hidrosmótica de la vejiga urinaria del sapo pueden ser disociados empleando colchicina, y mas evidentemente cuando el alcaloide es colocado junto con Cu⁺⁺.