ABSTRACT In southern Africa, oculocutaneous albinism (OCA) is the most common autosomal recessive disease amongst black Africans, occurring with a prevalence of approximately 1 in 3 900 individuals. OCA occurs in southern African Caucasoids with a frequency that reflects the European origins of this population, approximately 1 in 20-30 000. OCA type 1 is caused by mutations in the tyrosinase gene on chromosome 11q. Tyrosinase mutations occur in the Caucasoid population but are extremely rare in black Africans. OCA type 2 is caused by mutations in the P gene on chromosome 15q. P gene mutations occur in both the black and Caucasoid populations. A sub-type of OCA2 seen in black individuals, brown OCA (BOCA), is also caused by mutations at the P gene locus. A mutation screen was undertaken to identify disease-causing mutations in a group of OCA subjects from Sub-Saharan Africa. A common P gene mutation had been identified in the black population, a 2.7 kb intragenic deletion, accounting for 78% of P gene mutations in this group. No common tyrosinase mutations have been identified to date, in any population. A cohort of OCA subjects from South Africa, Lesotho, Zambia and the Central African Republic (CAR) were available for study in our laboratory. All subjects were screened for the 2.7 kb deletion mutation. Subjects homozygous for this mutation were excluded from further study. Subjects where one or two mutations remained to be identified were included in a mutation screen (63 blacks and 9 Caucasoids). Depending on the clinical categorisation of the type of albinism, subjects were screened for P gene mutations only (black OCA2) or were screened for P gene mutations and tyrosinase mutations (BOCA, unclassified black OCA and unclassified Caucasoid OCA). All 72 subjects were screened for P gene mutations and ten putative pathogenic mutations were identified. In the group of black OCA2 patients, four mutations which are likely to be pathogenic were found: A334V, 614delA, 683insT and 727insG. Mutations were identified in four individuals with an unusual hypopigmentation phenotype: E678K was found in the homozygous state in an individual from the CAR. A second individual was found to be a compound heterozygote for the I370T and the L688F mutations. A third individual was found to be heterozygous for the I370T mutation. Three P gene mutations were found in the Caucasoid sample: IVS 14-2 (a→g), V350M and P743L. No further mutations were identified in the BOCA sample. The P gene screen comprised 72 subjects, but 40 were heterozygous for the 2.7 kb deletion, therefore (144 minus 40 alleles) 104 alleles remained to be identified. Identification of 12/104 alleles means that a further 11.5% of the unknown P gene mutations are now accounted for. Thirty three of the 72 subjects were included in a further mutation screen – at the tyrosinase locus. Four mutations were identified, all in the Caucasoid group. Compound heterozygosity was shown in two individuals, one carrying the mutations, E294K and A490D and the other, P431T and T373K. Following mutation analysis of the P gene, it was apparent that a proportion of mutations did not lie in the coding region of the gene and it was proposed that some of the remaning unidentified mutations might be found in the 5’control or promoter region of the gene. At that time, sequence data for the region upstream of the P gene was not known, and so an attempt was made to clone the 5’region of the P gene. Two approaches were adopted – a bacterial artificial chromosome (BAC) known to contain this region was subcloned; and secondly, an inverse PCR experiment was undertaken. Neither experiment was successful in generating P gene promoter sequence. Variation at the P locus was investigated in a second context. This region of chromosome 15q was implicated as a host susceptibility locus for the infectious disease, tuberculosis (TB). A case-control study was undertaken to compare the frequencies of five intragenic, polymorphic markers in the P gene: the 2.7 kb deletion, the R305W polymorphism and the microsatellite markers, D15S1533, D15S1536 and D15S1537, between a group of black South African TB patients from Gauteng and healthy community controls and between a group of mixed-ancestry (Coloured) TB patients and healthy controls from the Western Cape region. Presence or absence of the 2.7 kb deletion mutation does not appear to influence susceptibility to TB in either the black or Coloured population samples studied here. The W allele of the R305W polymorphism is significantly (p<0.05) more common in the black patient group than in the black control group, suggesting it may be in linkage disequilibrium with a disease susceptibility allele. Microsatellite marker analysis showed that, in the black population, allele 18 at the D15S1533 locus is significantly (p<0.05) associated with susceptibility to TB. In the Cape Coloured population, alleles 20 and 27 at the D15S1533 locus, allele 12 at the D15S1536 locus and allele 16 at the D15S1537 locus are over represented in the patient group suggesting they may be markers for increased susceptibility to TB. Further, in the Coloured population alleles 12, 13 and 15 at the D15S1537 locus showed significant (p<0.05) association with normal controls and may be in linkage disequilibrium with protective or resistance alleles. The results of this study support the proposal of a TB susceptibility locus on chromosome 15q. OCA-causing mutations have been identified, but many remain elusive. Further characterisation of this region will give us a better understanding of the biological consequences of variation both within and around the P locus.

Thesis (M.A. (Clinical Psychology)) -- University of Limpopo, 2007 / This study explored the self-esteem of teenagers with oculocutaneous albinism and how they perceive societal attitudes towards them. A total of 40 teenage learners with oculocutaneous albinism from a special school and 60 teenage learners without the condition from the regular school in the Polokwane Municipality (Limpopo Province-South Africa) participated in the study. Qualitative and quantitative methods were triangulated in the study. Data were collected using the questionnaires and focus group discussions. The results revealed that teenagers with oculocutaneous albinism (experimental group) scored higher (Mean=36.08) than the control group (Mean=33.57) on the Rosenberg self-esteem scale. The study furthermore revealed that community members and teachers are perceived as having mixed (positive and negative) attitudes whereas family members and peers hold positive attitudes towards teenagers with oculocutaneous albinism. Although the teenagers with oculocutaneous albinism were found to have positive self-esteem, there is still a need for more organized community education programmes to educate the Black African communities about albinism.

Adaptation to any environment through the course of its evolution involves the alteration of multiple traits to ensure survival, Astyanax mexicanus is a notable example of this. Some of the most notable differences between the surface and cave populations are loss of pigmentation, decreased sleep, and reduced eyes. 208 surface – cave F2 hybrids were assessed for several morphological and behavioral phenotypes. There were significant differences found between pigmented and albino individuals, raising the question of a shared genetic basis for these traits. Oculocutaneous albinism 2 (oca2) is a notable contributor to albinism in many species, including A. mexicanus. Surface fish with CRISPR mutations at oca2 confirmed a contribution of oca2 in sleep loss within albino cavefish. Further, it was determined that oca2 is under selection and possibly has a pleiotropic function, which underlies the adaptive evolution of sleep loss and albinism. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

Heřmanský–Pudlák syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS-6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome-wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS. Clinical Trial registration:. Registrar: ClinicalTrials.gov. Website: www.clinicaltrials.gov. Registration Numbers: NCT00001456 and NCT00084305.

Background: Albinism affects approximately 1 in 17,000 individuals globally with the highest prevalence in SubSaharan Africa with an estimation of 1 in 2000 - 5000 live births and 1 in 2000 live births in Malawi. The total number of people living with albinism in Malawi is estimated to be 7000 - 10,000 of the total population. Albinism is a stigmatised condition particularly in Africa and children are particularly vulnerable. Purpose of the study: to explore and describe the experiences, perceptions and understanding of mothers who have children living with albinism in Malawi. Study design: Qualitative descriptive study. Data collection Methods: The study, conducted between June and July 2018 in Malawi, included voluntary participation of ten mothers 18 years and older who had children with albinism. Purposive sampling was used to select participants who met the inclusion criteria to answer the research question and achieve the purpose of the study. Semi structured interviews were conducted in the participants’ preferred language Chichewa. Interviews were audio recorded and transcribed. Data translation of the questionnaire from English to Chichewa was done by three different translators from Malawi using forward and backward translation. The same process was followed for translation of the data from the interviews. Data analysis: Thematic analysis guided the process of data analysis. Trustworthiness of the data analysis process was maintained. To ensure transparency in reporting the study and to allow replication, reporting guidelines from the equator Network were used to evaluate the quality of the study. The quality of semistructured interviews was evaluated by using the Consolidated Criteria for Reporting Qualitative Studies (COREQ), a 32-item checklist. The Standards for Reporting Qualitative Research (SRQR) were used to evaluate the quality of the completed study. Findings: Four themes emerged from the data: 1) stigmatisation, discrimination and harm, 2) Mothers’ impression of a child with albinism, 3) Mothers’ awareness of albinism and 4) Psychosocial effects of albinism. Conclusion: A description of the experiences and perceptions of mothers of children living with albinism in Malawi and their understanding of the condition has revealed that these children are stigmatised and unsafe in their communities and that these mothers experienced this acutely even though they were overwhelmingly positive about accepting and loving their children and attempted to protect them from harm whatever the cost. Being the first such reported Malawian study it has filled a gap in the existing knowledge in this field and provides a foundation for further research specific to people living with albinism in Malawi

The purpose of this study was to develop and describe a model for the enhancement of self-concept of people with oculocutaneous albinism based on the experience of the participants. The need to conduct the study was triggered by the researcher’s long-term interaction with people with oculocutaneous albinism, and observation that they are still stigmatised and marginalised by the community. A purposive sample of fifteen participants, consisting of twelve females and three males with oculocutaneous albinism, aged between 18 and 48, participated in the study. The study was conducted in urban and semi-urban areas around the Gauteng Province in South Africa. The study had two theory generative objectives, namely to identify the main concepts of the model from the findings, and to describe the model structure and process. A theory generative, qualitative, explorative, descriptive and contextual research design was used to achieve these objectives. Chinn and Kramer’s (1995:92) four steps of theory-generation were used, namely concept analysis, construction of theoretical relationships, description of the model, and development of guidelines to operationalise the model.Concept analysis involved identification, definition and classification of the concepts to develop the model. In-depth, phenomenological interviews were conducted to explore the participants’ experience. Data analysis and interpretation revealed three main themes from the findings: the participants’ perception of the self; experience with the external environment, and expression of need for development and growth. The main concepts deducted from the findings were “self-concept” and “enhancement” hence “A model for enhancement of self-concept of people with albinism”. Construction of theoretical relationships entailed using deductive reasoning to describe the interaction between the concepts of the model. Description of the model entailed visually portraying and describing the structure and process of the model, as well as evaluating it. Developing guidelines to operationalise the model entailed describing practical strategies to assist health professionals to enhance the self-concept of people with oculocutaneous albinism. / Health Studies / D. Litt. et Phil. (Health Studies)

The purpose of this study was to develop and describe a model for the enhancement of self-concept of people with oculocutaneous albinism based on the experience of the participants. The need to conduct the study was triggered by the researcher’s long-term interaction with people with oculocutaneous albinism, and observation that they are still stigmatised and marginalised by the community. A purposive sample of fifteen participants, consisting of twelve females and three males with oculocutaneous albinism, aged between 18 and 48, participated in the study. The study was conducted in urban and semi-urban areas around the Gauteng Province in South Africa. The study had two theory generative objectives, namely to identify the main concepts of the model from the findings, and to describe the model structure and process. A theory generative, qualitative, explorative, descriptive and contextual research design was used to achieve these objectives. Chinn and Kramer’s (1995:92) four steps of theory-generation were used, namely concept analysis, construction of theoretical relationships, description of the model, and development of guidelines to operationalise the model.Concept analysis involved identification, definition and classification of the concepts to develop the model. In-depth, phenomenological interviews were conducted to explore the participants’ experience. Data analysis and interpretation revealed three main themes from the findings: the participants’ perception of the self; experience with the external environment, and expression of need for development and growth. The main concepts deducted from the findings were “self-concept” and “enhancement” hence “A model for enhancement of self-concept of people with albinism”. Construction of theoretical relationships entailed using deductive reasoning to describe the interaction between the concepts of the model. Description of the model entailed visually portraying and describing the structure and process of the model, as well as evaluating it. Developing guidelines to operationalise the model entailed describing practical strategies to assist health professionals to enhance the self-concept of people with oculocutaneous albinism. / Health Studies / D. Litt. et Phil. (Health Studies)

Notre travail s’est intéressé à l’albinisme oculocutané en étudiant ses aspects clinico- moléculaires. Malgré l’analyse approfondie des gènes connus d’albinisme oculocutané, 15 % des patients restent sans mutation identifiée indiquant que les mutations sont situées dans des régions géniques non analysées par les techniques classiques de diagnostic moléculaire, ou qu’il existe d’autres gènes d’albinisme oculocutané. Nous avons établi une base de données clinico- biologiques décrivant les caractéristiques de plus de 400 patients analysés. Des outils de diagnostic moléculaire ont été développés à la recherche de mutations situées dans les introns et les régions régulatrices et de réarrangements géniques. Différentes stratégies ont également été utilisées pour rechercher des gènes candidats. La puce à façon a permis l’identification de grands réarrangements dans les gènes TYR, OCA2 et SLC45A2 et un réarrangement complexe du gène OCA2 chez 2 patients non apparentés. L'analyse de gènes candidats nous a permis d'identifier, chez 5 patients non apparentés présentant un albinisme oculocutané non syndromique, des mutations dans le gène SLC24A5, très récemment associé à l’AOC6. Le séquençage d’exome de 6 patients a mis en évidence des gènes candidats pour lesquels des analyses complémentaires sont poursuivies afin de confirmer leur implication dans la pathogenèse de l’AOC.Les résultats de ce travail permettent de redéfinir les aspects cliniques et moléculaires de l’AOC, d’identifier de nouveaux mécanismes moléculaires à l’origine de l’AOC ainsi que des gènes candidats dont la fonction dans le développement pigmentaire reste à élucider. L’identification de nouveaux gènes impliqués dans l’AOC pourrait permettre de mieux comprendre et de mieux prendre en charge les patients avec un AOC. / Our work focused on oculocutaneous albinism (OCA) by studying its clinical and molecular aspects. Despite a thorough analysis of the known genes involved in oculocutaneous albinism, 15% of patients remain without diagnostic at the molecular level indicating that mutations are located in unexplored regions and are undetected by standard techniques or that other genes are involved in albinism. We established a clinicomolecular database describing more than 400 patients and developped molecular tools in order to improve molecular diagnostic including a custom high resolution array-CGH dedicated to the four OCA genes (TYR, OCA2, TYRP1 and SLC45A2). We also used different strategies to identify new genes. Array-CGH allows us to detect large deletion in TYR, OCA2 and SLC45A2 and a complexe rearrangement in OCA2 in 2 unrelated patients. We identified, in 5 patients presenting with a non syndromic OCA, mutations in SLC24A5, recently associated with OCA6. Exome sequencing of 6 different patients allows us to identify candidate genes, for which further studies are required to confirm their involvement in OCA pathogenesis. The results of this work allowed us to delineate clinical and genetics aspects of more than 400 OCA patients and to identify new molecular mechanisms leading to OCA and candidates genes for which exact nature of their functions has to be understood. Giving the complexity of pigmentary system development and its regulation, identification of new genes leading to OCA could help to better understand OCA and take care of patients