mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome
We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu5) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu5 expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu5 positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (op...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Gogliotti, R. G., Senter, R. K., Rook, J. M., Ghoshal, A., Zamorano, R., Malosh, C., Stauffer, S. R., Bridges, T. M., Bartolome, J. M., Daniels, J. S., Jones, C. K., Lindsley, C. W., Conn, P. J., Niswender, C. M. Tags: ARTICLES Source Type: research

A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Bott, L. C., Badders, N. M., Chen, K.-l., Harmison, G. G., Bautista, E., Shih, C. C.- Y., Katsuno, M., Sobue, G., Taylor, J. P., Dantuma, N. P., Fischbeck, K. H., Rinaldi, C. Tags: ARTICLES Source Type: research

Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3{beta} activity
Parkinson's disease (PD) is a progressive neurodegenerative disorder that lacks a disease-modifying therapy. Leucine-rich repeat kinase 2 (LRRK2) was implicated as the most common genetic cause of PD. We previously established a LRRK2-G2019S Drosophila model that displayed the crucial phenotypes of LRRK2 parkinsonism. Here, we used a two-step approach to identify compounds from the FDA-approved licensed drug library that could suppress neurite degeneration in LRRK2-G2019S parkinsonism. Of 640 compounds, 29 rescued neurite degeneration phenotypes and 3 restored motor disability and dopaminergic neuron loss in aged LRRK2-G20...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Lin, C.-H., Lin, H.-I., Chen, M.-L., Lai, T.-T., Cao, L.-P., Farrer, M. J., Wu, R.-M., Chien, C.-T. Tags: ARTICLES Source Type: research

Drosophila clueless is involved in Parkin-dependent mitophagy by promoting VCP-mediated Marf degradation
PINK1/Parkin-mediated mitochondrial quality control (MQC) requires valosin-containing protein (VCP)-dependent Mitofusin/Marf degradation to prevent damaged organelles from fusing with the healthy mitochondrial pool, facilitating mitochondrial clearance by autophagy. Drosophila clueless (clu) was found to interact genetically with PINK1 and parkin to regulate mitochondrial clustering in germ cells. However, whether Clu acts in MQC has not been investigated. Here, we show that overexpression of Drosophila Clu complements PINK1, but not parkin, mutant muscles. Loss of clu leads to the recruitment of Parkin, VCP/p97, p62/Ref(2...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Wang, Z.-H., Clark, C., Geisbrecht, E. R. Tags: ARTICLES Source Type: research

BRCA2 minor transcript lacking exons 4-7 supports viability in mice and may account for survival of humans with a pathogenic biallelic mutation
This study provides the first in vivo evidence of the functional significance of a minor transcript of BRCA2 that can play a major role in the survival of humans who are homozygous for a clearly pathogenic mutation. Our results highlight the importance of assessing protein function restoration by premature truncating codon bypass by alternative splicing when evaluating the functional significance of variants such as nonsense and frame-shift mutations that are assumed to be clearly pathogenic. Our findings will impact not only the assessment of variants that map to this region, but also influence counseling paradigms and tr...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Thirthagiri, E., Klarmann, K. D., Shukla, A. K., Southon, E., Biswas, K., Martin, B. K., North, S. L., Magidson, V., Burkett, S., Haines, D. C., Noer, K., Matthai, R., Tessarollo, L., Loncarek, J., Keller, J. R., Sharan, S. K. Tags: ARTICLES Source Type: research

Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease
Elevated sweat chloride levels, failure to thrive (FTT), and lung disease are characteristic features of cystic fibrosis (CF, OMIM #219700). Here we describe variants in CA12 encoding carbonic anhydrase XII in two pedigrees exhibiting CF-like phenotypes. Exome sequencing of a white American adult diagnosed with CF due to elevated sweat chloride, recurrent hyponatremia, infantile FTT and lung disease identified deleterious variants in each CA12 gene: c.908-1 G>A in a splice acceptor and a novel frameshift insertion c.859_860insACCT. In an unrelated consanguineous Omani family, two children with elevated sweat chloride, i...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Lee, M., Vecchio-Pagan, B., Sharma, N., Waheed, A., Li, X., Raraigh, K. S., Robbins, S., Han, S. T., Franca, A. L., Pellicore, M. J., Evans, T. A., Arcara, K. M., Nguyen, H., Luan, S., Belchis, D., Hertecant, J., Zabner, J., Sly, W. S., Cutting, G. R. Tags: ARTICLES Source Type: research

Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome
Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generatio...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Hong, S., Hu, P., Marino, J., Hufnagel, S. B., Hopkin, R. J., Toromanovic, A., Richieri-Costa, A., Ribeiro-Bicudo, L. A., Kruszka, P., Roessler, E., Muenke, M. Tags: ARTICLES Source Type: research

Defective membrane fusion and repair in Anoctamin5-deficient muscular dystrophy
Limb-girdle muscular dystrophies are a genetically diverse group of diseases characterized by chronic muscle wasting and weakness. Recessive mutations in ANO5 (TMEM16E) have been directly linked to several clinical phenotypes including limb-girdle muscular dystrophy type 2L and Miyoshi myopathy type 3, although the pathogenic mechanism has remained elusive. ANO5 is a member of the Anoctamin/TMEM16 superfamily that encodes both ion channels and regulators of membrane phospholipid scrambling. The phenotypic overlap of ANO5 myopathies with dysferlin-associated muscular dystrophies has inspired the hypothesis that ANO5, like d...
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Authors: Griffin, D. A., Johnson, R. W., Whitlock, J. M., Pozsgai, E. R., Heller, K. N., Grose, W. E., Arnold, W. D., Sahenk, Z., Hartzell, H. C., Rodino-Klapac, L. R. Tags: ARTICLES Source Type: research

Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

Subscriptions Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

Front Cover
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - October 12, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research

Identification and function of enhancers in the human genome
The study of gene regulation has rapidly advanced by leveraging next-generation sequencing to identify and characterize the cis and trans elements that are critical for defining cell identity. These advances have paralleled a movement towards whole genome sequencing in clinics. These two tracks have increasingly synergized to underscore the importance of cis-regulatory elements in development as well produce countless studies implicating these elements in human disease. Other studies have emphasized the clinical phenotypes associated with variation or mutations in trans factors, including non-coding RNAs and chromatin regu...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Coppola, C. J., C. Ramaker, R., Mendenhall, E. M. Tags: INVITED REVIEWS Source Type: research

Mission critical: the need for proteomics in the era of next-generation sequencing and precision medicine
Next generation sequencing (NGS) has ignited an unprecedented pace of discovery in the biomedical sciences that is fundamentally transforming the way that we understand, diagnose and treat disease, and has motivated the belief that true precision medicine – medicine that is tailored to an individual’s genetic, biochemical and exposure profile – will be a reality in the near term. With minimal sample requirement, NGS can enable the concurrent genome-wide study of genetic variations, transcriptomes, and certain epigenetic modifications. However, interrogating proteins as efficiently as DNA and RNA can be in...
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Cayer, D. M., Nazor, K. L., Schork, N. J. Tags: INVITED REVIEWS Source Type: research

Disease modelling using human iPSCs
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - September 24, 2016 Category: Genetics & Stem Cells Authors: Chamberlain, S. J. Tags: INVITED REVIEWS Source Type: research