Outline:

• Introduction: 1/17,000 people have died from albinism disease.
• Four types TYP, OCA2, TYRP1, and MATP.
• Definition: OCA related to skin cancer. Reduce vision. Symptoms: white skin, hair, and eyes. Absent in melanin.
• Inherited. Especially from mother.
• OCA2 is the most serious
• Especially in Africa.
• Genetic synthesis: 2 separate mutations.
• Mutation in P-gene: 24 exons (23 coded) and membrane transporter (838 amino acids).
• Test on OCA2:  responsible for glutathione, tyrosine, and protons.
• Gene deficiency and consequently
• Molecular genetic testing: mutation examination of genes using common screening like single strand to test on DNA sequence.
• Test on TYR: identical to exons 4, 5
• Test on tyrosinase: 529 amino acids.5 exons.
• Unresolved question: Missing heritability.
• Partial vs complete albinism
• Explain to the question of missing heritability.
• Explore 22 novel genes.
• Structure and function in OCA gene, TYR sensitive to temperature.
• Methods:
• 52 patients.
• 2 groups: total albinism vs partial albinism
• Result:
• 21 found 2 trans mutations in total albinism
• 19 has 2 mutations
• From proband and mother
• Stop codons to nonsense-mediated decay
• Exons 18’ partial deletion
• Add 42 base to an intron, subtract 12 based on exon 18’ 3’ end
• Result in NMD

Introduction: It has been estimated that 1/17,000 patients worldwide are affected by some form of albinism. With albinism patients, skin cancer might become more common. All four different subtypes of OCA are autosomal recessive diseases. The various disease categories are caused by at least four genes (TYP, OCA2, TYRP1, and MATP). Ocular albinism, Hermansky- Pudlak, Chediak-Higashi, Griscelli, and Waardenburge syndrome type II are the most common diagnoses. When the disease-causing mutations have been found in the family, carrier screening and prenatal diagnosis are both achievable.

Definition and Description: OCA stands for Oculocutaneous albinism and is also known as a collection of 4 autosomal recessive diseases. Its characteristics are hypopigmented on skin, hair, and the eye due to the absence of melanin. Reduced visual acuity is the result of misdirected optic nerve fibers, and foveal hypoplasia, which is brought on by decreased melanin in the eyes. The type of OCA affects how much hypopigmentation there is in the skin and hair. Albinism has received a great deal of research and can affect afflict persons from many ethnic backgrounds. The many founder mutations in different genes help to explain why there are so wide regional variations in the incidence of the different kinds of albinism. It common in African patients. According to the paper, “It affects 1 in 3,900 of the population in some parts of the southern part of Africa” (Gronskov 2007). The milder types, OCAB, OCA1, OCA3, OCA4, exhibit some pigment buildup. The most common kind worldwide is OCA2.

Genetic synthesis: The majority of patients have two separate gene mutations or are compound heterozygotes. The most important is the OCA2 phenotype (MIM 203200) is brought on by mutations in the P-gene. This gene includes 24 exons (of which 23 are coding), and an integral membrane transporter protein with 838 amino acids is produced from OCA2 mRNA albeit its function is unknown. By preserving an acidic pH in melanosomes, OCA2 appears to exert at least some of its effects.

In the past, theories on the role of OCA2 have mostly concentrated on possible transport functions involving glutathione, tyrosine, and protons. Tyrosinase must normally be transported to the melanosome by OCA2. Tyrosinase builds up in the trans-Golgi networks. The peptide is transported to the plasma membrane and ultimately released from the cells, as a result of abnormalities in COA2, according to in vitro studies using mouse and human melanocytes. Clinically, OCA2 and OCA1B exhibit significant overlap, which typically results in partial OCA.

Tyrosinase, an enzyme with 529 amino acids, is coded for by its 5 exons. Tyrosinase is known as a type 1 transmembrane monophenol monooxygenase. The first and second reaction crucial is the hydroxylation of tyrosine to L-DOPA, and the oxidation of L-DOPA to DOPA quinone are among the several steps in the synthesis of melanin that are catalyzed by tyrosinase.

In addition to the typical ocular symptoms, OCA’s diagnosis identifies on the clinical basis finding of hypopigmentation in skin, and hair. However, molecular testing is required to determine the gene deficiency and consequently. The foundation of molecular genetic testing is the mutational examination of these genes using common screening techniques like single-strand conformational polymorphism or denatured highly powerful liquid chromatography followed by DNA sequencing. In order to support the likely harmful effect of a mutation, chromosomal control analysis. Amino acid silico studies are required because mutational analysis of OCA2 is challenging due to the existence of multiple polymorphisms

 The existence of pseudogenes with sequences very identical to exons 4 and 5 of TYR makes the mutational study of TYR challenging. This can be avoided by either using specialized primer that exclusive amplify TYR sequences or by first digesting pseudogene sequences with restriction enzyme before PCR amplification. Depending on the residual activity, TYR mutations might result in either a full or partial OCA.

Unresolved questions and new discoveries: After all four OCA genes have been known, a sizable portion of the OCA cases remain genetically unexplained. The size of “missing heritability” (MH) estimates varies across investigations. Individuals with partial albinism are probably more likely to have missing heritability than patients with complete albinism. 10 to 25 percent of full albinism cases cannot be explained by pair, trans-oriented mutations in recognized genes. In some populations, the percentage of people with partial albinism could reach 50%.

The authors state: “However, in our experience, many individuals with albinism are interested in their genotype for validation of the diagnosis, genetic counseling, and prognosis” (Simeonov 2013).

 The account for the absence of heredity in OCA, several theories have been proposed according to Simeonov’s team researchers: 1) as yet unidentified OCA gene; 2) a variant in the promoter or other regulatory element not detected or recognized by current sequencing strategies; 3) epistatic or synergistic heterolysis relationships between known genes; 4) dominant mutations that are not recognized as pathogenic due to ethnic/pigmentation background; 5) unrecognized splicing mutations, and 6) unrecognized large deletion that is not detected by sanger Lack of functional confirmation of many reported TYR variation (Simeonov 2013). In the article written by Simeonov and his team, they introduced 22 novel mutations. The important result that they state are structure related in and among these OCA genes, clinical issues related to OCA, TYR temperature sensitivity, ‘missing heritability’ in OCA, and find out abnormal variants and genes.

Methods: They examined their OCA cohort to see if there were any different rates of ‘missing heritability’ between complete albinism and partial albinism patients. 52 patients out of 61 patients were examined. They lacked phenotypic data for four patients who had not been seen at their facility. Due to their OA-like phenotype and unusual pedigree that suggested dominant inheritance, another family was disqualified. Four siblings were eliminated to produce a cohort that was entirely independent. Based on clinical examination, they divided the patients into two groups: those with little to no pigmentation and people with traced or partial pigmentation. Then, they compare the percentage of each group to identify 2 trans mutations.

Results: In the albinism group, 21/23 patients have two trans mutations (91%). In the Partial albinism group, 19/29 patients have two trans mutations (61%). They repeated the exon sequencing from a wider amplicon to examine the probability of allele dropout. A heterozygous SNP was discovered in a primer binding region in the proband, and mother in the adjustment segregation of polymorphisms. Additionally, they found the proband to have the typical, mother-inherited mutation.

Of the total of 14 mutations in TYR, 5 of them have premature stop codons. They also are the object of misconduct-mediated decay. In OCA2, they discovered 5 new mutations. Exon 18’s partial deletion, caused by a microhomology of four nucleotides, was another mutation. Since the deletion adds 42 bases to the neighboring intron and subtracts 12 bases from exons 18’s 3’ end. It is likely to result in the NMD of the transcript.

References

Gronshov, K., Ek, J., Brondum-Nielsen, K. Oculocutaneous albinism. Orphanet J Rare Dis. 2, 43 (2007).

Simeonov, D. et al. DNA Variations in Oculocutaneous Albinism: An Updated Mutation List and Current Outstanding Issues in Molecular Diagnostics. Hum Mutat 34, 827-835(2013).