Global Awakening in Genetic Counseling

The article by Ricki Lewis, Nature, Volume 449,October 18, 2007, correctly points out that the genetic counseling profession is on the "verge of being discovered by the rest of the world". The rapid recognition of genes associated with single-gene disorders and complex conditions has deepened our understanding of the role of genetics in health and illness. The impact of genetic conditions on individuals and families, particularly in ethical, legal and psychosocial arenas, requires specially trained professionals to work in this unique and growing dimension of healthcare. The Transnational Alliance for Genetic Counseling (TAGC) represents fifteen countries currently providing genetic counselor education across five continents

A Founder Mutation in MYO7A Underlies a Significant Proportion of Usher Syndrome in Indigenous South Africans: Implications for the African Diaspora

PURPOSE. Research over the past 25 years at the University of Cape Town has led to the identification of causative mutations in 17% of the 1416 families in the Retinal Degenerative Diseases (RDD) biorepository in South Africa. A low rate of mutation detection has been observed in patients of indigenous African origin, hinting at novel genes and mutations in this population. Recently, however, data from our translational research program showed two unrelated indigenous African families with Usher syndrome (USH), with the same homozygous MYO7A mutation. Therefore, the extent to which this mutation contributes toward the disease burden in South Africa was investigated. METHODS. Cohorts of unrelated indigenous South African probands with different RDD diagnoses were tested for the MYO7A c.6377delC mutation. Familial cosegregation analysis was performed for homozygous probands, clinical data were evaluated, and SNP haplotypes were analyzed. RESULTS. This homozygous MYO7A mutation underlies a remarkable 43% of indigenous African USH cases investigated in this study, the majority of which (60%) were diagnosed clinically with Type 2 USH. All homozygotes shared a common haplotype. This mutation does not appear to cause nonsyndromic vision loss. CONCLUSIONS. Of interest is the origin of this common mutation relevant to the Bantu population migration into southern Africa. Further investigation of the phenotype may elucidate the disease biology, and perhaps reveal a larger cohort with the same mutation, with which to assess the impact of environmental and genetic modifiers and evaluate therapeutic trials

Polyglutamine disease: from pathogenesis to therapy

Polyglutamine diseases are inherited neurodegenerative conditions arising from expanded trinucleotide CAG repeats in the disease-causing gene, which are translated into polyglutamine tracts in the resultant protein. Although these diseases share a common type of mutation, emerging evidence suggests that pathogenesis is complex, involving disruption of key cellular pathways, and varying with the disease context. An understanding of polyglutamine disease mechanisms is critical for development of novel therapeutics. Here we summarise theories of molecular pathogenesis, and examine ways in which this knowledge is being harnessed for therapy, with reference to work under way at the University of Cape Town. Despite a plethora of preclinical data, clinical trials of therapies for polyglutamine diseases have had only limited success. However, recently initiated trials, including those using gene silencing approaches, should provide valuable insights into the safety and efficacy of therapies directly targeting polyglutamine pathogenesis. This is particularly relevant in the South African context, where the frequencies of two polyglutamine diseases, spinocerebellar ataxia types 1 and 7, are among the highest globally

Foreword

In 2014, four of Emeritus Prof. Peter (fondly known as PB) Beighton’s past PhD students decided that they would like to honour him for his leadership and the influence that he had on their professional lives, and collaborated on a project to compile a Festschrift in his honour. They are Prof. Michael Hayden, now living in Canada, the first PhD graduate that PB supervised in 1979, together with Profs Jacquie Greenberg from the University of Cape Town (UCT), Alan Bryer from UCT and Groote Schuur Hospital (GSH), and Lawrence Stephen from the University of the Western Cape (UWC). Prof. Lawrence Stephen was the last PhD graduate that Prof. Beighton supervised before he officially retired in 1999.Many colleagues who have worked over the past 5 decades and who continue to work with him were invited to contribute to this supplement to the SAMJ. The Festschrift includes the history behind Peter Beighton, who was born, grew up and trained in the UK and came to UCT in 1972. His legacy includes the impact that he made on those who trained under him in SA, as well as throughout the world. The Festschrift includes the history of genetics and current genetic practice in South Africa, as well as the influence that he has had on medical genetics in general, dental genetics and now genomics going into the new millennium. Tributes have been received from people all over the world, attesting to his outstanding leadership and mentorship, and highlight how he influenced the climate, growth and development of genetics at UCT, and scientific and technological fields in genetics and genomics over the past few decades.This Foreword includes a message from Emeritus Prof. Stuart Saunders – former Head of Department (HoD) of Medicine at GSH in the 1970s when PB arrived at UCT – followed by some words from Emeritus Prof. J P van Niekerk, former Dean of the UCT Faculty of Health Sciences in the 1980s. Profs Greenberg, Bryer and Stephen conclude the Foreword, while Prof. Hayden introduces the legacy that Prof. Beighton has passed on

Management of a South African family with retinitis pigmentosa—should potential therapy influence translational research protocols?

Mutation analysis of retinal candidate genes is performed as part of an ongoing research to identify the causative genetic defect in South African families with retinal degenerative disorders (RDDs). A translational research protocol has been established whereby probands are counseled and given their molecular genetic results to take back to other family members, who can then request individual diagnostic testing. A Thr17Met mutation of the rhodopsin gene was identified in a Caucasian South African family with autosomal dominant retinitis pigmentosa. Patients with this mutation appear to benefit from treatment using oral vitamin A supplementation. This family has been informed that a molecular diagnosis is available; however, one individual has refused testing and none of the younger generation has shown interest in receiving molecular results or genetic counseling. Adapting the established protocol for the translation of RDD research results and contacting mutation positive individuals may be justifiable in light of the potential benefit of therapy

Design of RNAi Hairpins for Mutation-Specific Silencing of Ataxin-7 and Correction of a SCA7 Phenotype

Spinocerebellar ataxia type 7 is a polyglutamine disorder caused by an expanded CAG repeat mutation that results in neurodegeneration. Since no treatment exists for this chronic disease, novel therapies such post-transcriptional RNA interference-based gene silencing are under investigation, in particular those that might enable constitutive and tissue-specific silencing, such as expressed hairpins. Given that this method of silencing can be abolished by the presence of nucleotide mismatches against the target RNA, we sought to identify expressed RNA hairpins selective for silencing the mutant ataxin-7 transcript using a linked SNP. By targeting both short and full-length tagged ataxin-7 sequences, we show that mutation-specific selectivity can be obtained with single nucleotide mismatches to the wild-type RNA target incorporated 3′ to the centre of the active strand of short hairpin RNAs. The activity of the most effective short hairpin RNA incorporating the nucleotide mismatch at position 16 was further studied in a heterozygous ataxin-7 disease model, demonstrating significantly reduced levels of toxic mutant ataxin-7 protein with decreased mutant protein aggregation and retention of normal wild-type protein in a non-aggregated diffuse cellular distribution. Allele-specific mutant ataxin7 silencing was also obtained with the use of primary microRNA mimics, the most highly effective construct also harbouring the single nucleotide mismatch at position 16, corroborating our earlier findings. Our data provide understanding of RNA interference guide strand anatomy optimised for the allele-specific silencing of a polyglutamine mutation linked SNP and give a basis for the use of allele-specific RNA interference as a viable therapeutic approach for spinocerebellar ataxia 7