Effects of congenital cataract mutation R116H on αA-crystallin structure,function and stability

α-crystallin is a molecular chaperone that maintains the optical properties of the lens and delays the onset scattering caused by aging-related protein aggregation. In this research, we found that the missense mutation R116H resulted in an altered size distribution, impaired packing of the secondary structures and modified quaternary structure with great hydrophobic exposure. The mutant exhibited a substrate-dependent chaperone (aggregation–inhibition) or anti-chaperone (aggregation–promotion) effect. Equilibrium unfolding experiments indicated that the mutation stabilized an aggregation-prone intermediate which was not populated during the unfolding of the wild-type protein. The accumulation of this intermediate greatly promoted the formation of non-native large oligomers or aggregates during unfolding. These results suggested that both the aggregation of the mutant upon stress and co-deposition with the target proteins were likely to be responsible for the onset of cataract.     

Identification and functional characterization of a novel splicing mutation in RP gene PRPF31

A six-generation Chinese family with autosomal dominant retinitis pigmentosa (adRP) was identified and characterized. Genome-wide linkage analysis linked the family to markers D19S601 to D19S605, which span the PRPF31 gene on chromosome 19q13.33-13.43 (RP11) (LOD = 5.03). Direct DNA sequence analysis identified a novel splicing mutation (IVS1+1G>T) in affected family members and carriers, but not in unaffected family members and 200 normal controls. The splicing mutation occurs at the splicing donor of intron 1. Real time PCR with lymphoblastoid RNA samples from family members showed that in comparison to normal family members, the splicing mutation reduced the expression level of the PRPF31 mRNA by 57% in symptomatic patients and by 28% in clinically asymptomatic carriers. Our studies identify a novel splicing mutation in PRPF31 associated with adRP and suggest that the penetrance of RP11 mutations may be correlated with the expression level of the PRPF31 mRNA.     

Inherited copper toxicosis with emphasis on copper toxicosis in Bedlington terriers

Canine copper toxicosis is an important inherited disease in Bedlington terriers, because of its high prevalence rate and similarity to human copper storage disease. It can lead to chronic liver disease and occasional haemolytic anaemia due to impaired copper excretion. The responsible gene for copper toxicosis in Bedlington terriers has been recently identified and was found not to be related to human Wilson’s disease gene ATP7B. Although our understanding of copper metabolism in mammals has improved through genetic molecular technology, the diversity of gene mutation related to copper metabolism in animals will help identify the responsible genes for non-Wilsonian copper toxicoses in human. This review paper discusses our knowledge of normal copper metabolism and the pathogenesis, molecular genetics and current research into copper toxicosis in Bedlington terriers, other animals and humans.     

Dental anthropology. By Juraj Kallay. Tisak: Izdavački zavod Jugoslavenske akademije,Zagreb. x + 181 pp. 459 figures,tables, bibliography,index. N.p.

Exceptions have been cited which rule against the simple autosomal recessive hypothesis for the transmission of susceptibility to infection with Australia antigen (HBsAg). An attempt is made here to present a genetic model for a complex segregation analysis of a new and unique set of data to test this hypothesis. Regression techniques were used to estimate in four populations, age and sexspecific penetrance levels and the frequency of the gene whose product is hypothesized to be HBsAg. While the genetic hypothesis was not in general supported, observed deviations and their possible causes are discussed.     

Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss

Hearing loss is the most frequent sensory disorder. It affects 3 in 1000 newborns. It is genetically heterogeneous with 60 causally-related genes identified to date. Mutations in GJB2 gene account for half of all cases of non-syndromic deafness. The aim of this study was to determine the relative frequency of GJB2 allele variants in Tunisia. In this study, we screened 138 patients with congenital hearing loss belonging to 131 families originating from different parts of Tunisia for mutations in GJB2 gene. GJB2 mutations were found in 39% of families (51/131). The most common mutation was c.35delG accounting for 35% of all cases (46/131). The second most frequent mutation was p.E47X present in 3.8% of families. Four identified mutations in our cohort have not been reported in Tunisia; p.V37I, c.235delC, p.G130A and the splice site mutation IVS1+1G>A (0.76%). These previously described mutations were detected only in families originating from Northern and not from other geographical regions in Tunisia. In conclusion we have confirmed the high frequency of c.35delG in Tunisia which represents 85.4% of all GJB2 mutant alleles. We have also extended the mutational spectrum of GJB2 gene in Tunisia and revealed a more pronounced allelic heterogeneity in the North compared to the rest of the country.     

Phenotypic spectrum in uniparental disomy: Low incidence or lack of study?

CONTEXT:

Alterations in the human chromosomal complement are expressed phenotypically ranging from (i) normal, via (ii) frequent fetal loss in otherwise normal person, to (iii) sub-clinical to severe mental retardation and dysmorphism in live births. A subtle and microscopically undetectable chromosomal alteration is uniparental disomy (UPD), which is known to be associated with distinct birth defects as per the chromosome involved and parental origin. UPD can be evident due to imprinted genes and/or activation of recessive mutations.

AIMS:

The present study comprises of data mining of published UPD cases with a focus on associated phenotypes. The goal was to identify non-random and recurrent associations between UPD and various genetic conditions, which can possibly indicate the presence of new imprinted genes.

SETTINGS AND DESIGN:

Data mining was carried out using the homepage “http://www.fish.uniklinikum-jena.de/UPD.html.”, an online catalog of published cases with UPD.

MATERIALS AND METHODS:

The UPD cases having normal karyotype and with or without clinical findings were selected to analyze the associated phenotypes for each chromosome, maternal or paternal involved in UPD.

RESULTS:

Our results revealed many genetic conditions (other than the known UPD syndromes) to be associated with UPD. Even in cases of bad obstetric history as well as normal individuals chance detection of UPD has been reported.

CONCLUSIONS:

The role of UPD in human genetic disorders needs to be studied by involving larger cohorts of individuals with birth defects as well as normal population. The genetic conditions were scrutinized in terms of inheritance patterns; majority of these were autosomal recessive indicating the role of UPD as an underlying mechanism.     

Emerging roles of MCPH1: Expedition from primary microcephaly to cancer

Genetic mutations in microcephalin1 (MCPH1) cause primary autosomal recessive microcephaly which is characterized by a marked reduction in brain size. MCPH1 encodes a centrosomal protein with three BRCT (BRCA1 C-terminal) domains. Also, it is a key regulator of DNA repair pathway and cell cycle checkpoints. Interestingly, in the past few years, many research studies have explored the role of MCPH1, a neurodevelopmental gene in several cancers and its tumor suppressor functions have been elucidated. Given the diverse new emerging roles, it becomes critical to review and summarize the multiple roles of MCPH1 that is currently lacking in the literature. In this review after systematic analysis of literature, we summarise the multiple functional roles of MCPH1 in centrosomal, DNA repair and apoptotic pathways. Additionally, we discuss the considerable efforts taken to understand the implications of MCPH1 in diseases such as primary microcephaly and its other emerging association with cancer and otitis media. The promising view is that MCPH1 has distinct roles and its clinical associations in various diseases makes it an attractive therapeutic target.     

Genetic analysis of feeding preference in two related species of Altica (Coleoptera: Chrysomelidae: Alticinae)

Abstract 1. Genetic analysis of feeding preference can make an important contribution to our understanding of the evolution of host‐plant selection in phytophagous insects. Two closely related flea beetles, Altica viridicyanea (Baly) and Altica fragariae Nakane, with separate host plants [Geranium wilfordii Maxim. and Duchesnea indica (Andrews) Focke respectively] were hybridised to analyse the inheritance mode of feeding preference. 2. Adult hybrid F₁ (A. viridicyanea female × A. fragariae male) preferred G. wilfordii to D. indica in two‐choice tests, regardless of which plant they had fed on as larvae. Adults of one backcross to A. fragariae preferred D. indica to G. wilfordii, and the two backcrosses to A. viridicyanea consumed only a very small percentage of D. indica. Adult females of F₂ showed no significant preference, whereas males of F₂ showed slight preference for G. wilfordii over D. indica. 3. Both the mean feeding preference and the segregation pattern of beetles indicate that the feeding preference of A. viridicyanea and A. fragariae for G. wilfordii and D. indica, respectively, is mainly controlled by a major dominant autosomal gene (or several genes). 4. The variance between feeding preference and oviposition preference of female F₂ indicate that the two behaviour traits of Altica species are controlled by different gene(s).     

Epigenetics and autosomal dominant polycystic kidney disease

The roles of epigenetic modulation of gene expression and protein functions in autosomal dominant polycystic kidney disease (ADPKD) have recently become the focus of scientific investigation. Evidence generated to date indicates that one of the epigenetic modifiers, histone deacetylases (HDACs), are important regulators of ADPKD. HDACs are involved in regulating the expression of the Pkd1 gene and are the target of fluid flow-induced calcium signal in kidney epithelial cells. Pharmacological inhibition of HDAC activity has been found to reduce the progression of cyst formation and slow the decline of kidney function in Pkd1 conditional knockout mice and Pkd2 knockout mice, respectively, implicating the potential clinical application of HDAC inhibitors on ADPKD. Since the expression of HDAC6 is upregulated in cystic epithelial cells, the potential roles of HDAC6 in regulating cilia resorption and epidermal growth factor receptor (EGFR) trafficking through deacetylating α-tubulin and regulating Wnt signaling through deacetylating β-catenin are also discussed. This article is part of a Special Issue entitled: Polycystic Kidney Disease.