MKS3/TMEM67 mutations are a major cause of COACH syndrome, a joubert syndrome related disorder with liver involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/ aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

The node of Ranvier in CNS pathology.

Healthy nodes of Ranvier are crucial for action potential propagation along myelinated axons, both in the central and in the peripheral nervous system. Surprisingly, the node of Ranvier has often been neglected when describing CNS disorders, with most pathologies classified simply as being due to neuronal defects in the grey matter or due to oligodendrocyte damage in the white matter. However, recent studies have highlighted changes that occur in pathological conditions at the node of Ranvier, and at the associated paranodal and juxtaparanodal regions where neurons and myelinating glial cells interact. Lengthening of the node of Ranvier, failure of the electrically resistive seal between the myelin and the axon at the paranode, and retraction of myelin to expose voltage-gated K(+) channels in the juxtaparanode, may contribute to altering the function of myelinated axons in a wide range of diseases, including stroke, spinal cord injury and multiple sclerosis. Here, we review the principles by which the node of Ranvier operates and its molecular structure, and thus explain how defects at the node and paranode contribute to neurological disorders

Epileptic source localization using wavelet prefiltering and MUSIC scanning

The epileptic focus localization in the 3-D brain structure is performed using integer spline wavelet prefiltering and source localization. The forward and inverse problems are solved by Boundary Element Method (BEM) and MUSIC (Multiple Signal Classification) Scanning algorithm, respectively. The realistic head model is obtained by using an average human MRI data released by the Montreal Neurological Institute (MNI). 19 Channel EEG data from three different patients are collected. The technique is tested on these three clinical cases with secondary epileptic seizures based on morphological lesions that could be depicted in the anatomical MRI examinations of the patients. The estimated locations of the generators of interictal epileptiform signals correspond well to the surrounding neural tissue of the lesions. Especially, the disappearance of the seizures in two operated patients after the removal of the astrocytomas verifies the results. The wavelet prefiltering facilitates the visual inspection and detection of the interictal epileptic spikes and the BEM based on a realistic head model gives a more accurate anatomical localization for the focus. A focal source model is widely accepted in many cases of epilepsy and the MUSIC scanning seems to be very suitable for localizing these type of sources

Local biotransformation of methanol by retinal and optic nerve mitochondria and induction of mitochondrial permeability transition pores by related toxicants

[No Abstract Available]This study was supported by Aliye Uster Foundation. Akbiyik Et (R) was acknowledged for providing the fresh bovine eyes and optic nerve tissues.Aliye Uster Foundatio