What is Albinism?
 

Albinism is a rare genetic disorder primarily caused by a deficiency or reduced function of the enzyme tyrosinase, leading to impaired melanin synthesis. This manifests as a lack of pigment in the skin, hair, and eyes. Due to the absence of melanin's protective role, patients are highly susceptible to ultraviolet damage and often experience severe visual impairments. The global incidence of albinism is approximately 1 in 17,000 to 1 in 20,000, with an estimated 70,000 patients in China.
 

Pathogenesis
 

The pathogenesis of albinism is mainly related to defects in tyrosinase, a key enzyme in the melanin synthesis pathway. Tyrosinase is the rate-limiting enzyme that initiates melanin production, catalyzing the conversion of tyrosine to DOPA and subsequently to melanin. Mutations in the tyrosinase gene (TYR) result in reduced or completely absent enzyme activity, disrupting melanin synthesis and causing albinism.

Based on clinical presentation, albinism is primarily classified into two major types:

1. Oculocutaneous Albinism (OCA): Accounts for approximately 90% of albinism cases, making it the most common type. Patients lack pigment in the skin, hair, and eyes.

Seven different non-syndromic recessive OCA forms have been identified:

● OCA1: Associated with mutations in the tyrosinase gene (TYR).

● OCA2: Associated with mutations in the OCA2 gene (formerly known as the P gene).

● OCA3: Associated with mutations in the tyrosinase-related protein 1 gene (TYRP1).

● OCA4: Associated with mutations in the solute carrier family 45 member 2 gene (SLC45A2, formerly known as MATP).

● OCA5: Mapped to chromosome 4q24, but the specific gene has not yet been identified.

● OCA6: Associated with mutations in the solute carrier family 24 member 5 gene (SLC24A5).

● OCA7: Associated with mutations in the c10orf11 gene.

Generally, all forms of albinism result, directly or indirectly, from dysfunctional TYR, which catalyzes the first step of melanin synthesis. Indirect causes include abnormal folding of TYR, inefficient targeting of TYR to melanosomes (the melanin-producing organelles), and/or an unfavorable biochemical environment for TYR function within melanosomes.

(Image: PubMed)

2. Ocular Albinism (OA): Characterized by a lack of pigment only in the eyes, with normal skin and hair color. Causative genes include GPR143 and AROA.

Additionally, a small number of patients may present with associated syndromes, such as Chediak-Higashi Syndrome (CHS) (immunodeficiency) and Hermansky-Pudlak Syndrome (HPS) (bleeding tendency). The causative gene for CHS is LYST. HPS involves up to 10 causative genes: HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, BLOC1S6, and AP3D1.

The types of gene mutations in albinism are predominantly point mutations, including missense, nonsense, frameshift, and splice-site mutations.
 

(Image: PubMed)

Gene Therapy
 

● AAV Vector Delivery of Normal Gene: Utilizes adeno-associated virus (AAV) vectors to deliver a functional TYR gene into patient cells, aiming to restore tyrosinase activity. A 2022 study published in Nature Communications demonstrated successful improvement of hair pigmentation in a mouse model using AAV vectors.

● Gene Editing Technology: Aims to directly repair the mutated gene, potentially avoiding long-term dependence on exogenous gene expression. Feasibility has been validated in in vitro cell experiments.

● Stem Cell Therapy: Involves differentiating gene-modified induced pluripotent stem cells (iPSCs) into melanocytes for transplantation into patient skin or retina, offering potential for long-term therapeutic effects for albinism patients.

Mouse Models

● TYR Knockout Mice: Completely lack tyrosinase, presenting with generalized albinism. Commonly used to study OCA1.

● OCA2 Knockout Mice: Model OCA2, characterized by abnormal melanosome pH leading to pigment synthesis impairment.

● Dct⁻¹ Mice: Used to study melanocyte development and melanin synthesis.

● Tyrc-2J/c-2J Mice: Carry a tyrosinase gene mutation (c.G291T, p.R77L), exhibiting generalized albinism.

● Tyrc-h/c-h Mice: Carry a tyrosinase gene mutation (c.A1259G, p.H420R), used to study tyrosinase dysfunction.

● Tyrp1 KO Mice: Knockout of the tyrosinase-related protein 1 gene (TYRP1), modeling OCA3.

● Tyrp1b-J Mice: Carry the c.403T>A and 404delG mutations in Tyrp1, used to study OCA3.

● Pun Mice: A core model for studying Oculocutaneous Albinism type 2 (OCA2); the mutation leads to abnormal melanosome pH regulation.

● Hps1ep Mice: Exhibit characteristic HPS symptoms like platelet dysfunction and pulmonary fibrosis.

● 4L/PS-NA Mice: Combine the Gba1 V394L mutation with prosaposin knockout, resulting in a severe neuropathic form of albinism, modeling a rare OCA subtype with neurological symptoms.

● Hps1ep/Hps1ep Mice: Used to study albinism caused by HPS1 gene mutations.

● Ap3b1pe/Ap3b1pe Mice: Used to study albinism caused by AP3B1 gene mutations.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various albinism mouse models according to client needs, such as TYR knockout mice, OCA2 knockout mice, Dct⁻¹ mice, Tyrc-2J/c-2J mice, Tyrc-h/c-h mice, Tyrp1 KO mice, Tyrp1 b-J mice, Pun mice, Hps1ep mice, 4L/PS-NA mice, Hps1ep/Hps1ep mice, Ap3b1pe/Ap3b1pe mice, etc. We welcome inquiries!
 

References:

[1] Tingaud-Sequeira A, Mercier E, Michaud V, Pinson B, Gazova I, Gontier E, Decoeur F, McKie L, Jackson IJ, Arveiler B, Javerzat S. The Dct-/- Mouse Model to Unravel Retinogenesis Misregulation in Patients with Albinism. Genes (Basel). 2022 Jun 27;13(7):1164. doi: 10.3390/genes13071164. PMID: 35885947; PMCID: PMC9324463.

[2] Zhang Yingzhen, Jin Caihong, Li Donglu. Research Progress on Clinical Symptoms and Molecular Mechanisms of Albinism. International Journal of Genetics, 2022, 45(1): 31-37. DOI: 10.3760/cma.j.cn231536-20210722-00096.

[3] Thomas MG, Zippin J, Brooks BP. Oculocutaneous Albinism and Ocular Albinism Overview. 2023 Apr 13. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

[4] Wu, Y., Wan, X., Zhao, D. et al. AAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa. Nat Commun 14, 4923 (2023). https://doi.org/10.1038/s41467-023-40655-6

[5] Guttentag SH, Akhtar A, Tao JQ, Atochina E, Rusiniak ME, Swank RT, Bates SR. Defective surfactant secretion in a mouse model of Hermansky-Pudlak syndrome. Am J Respir Cell Mol Biol. 2005 Jul;33(1):14-21. doi: 10.1165/rcmb.2004-0293OC. Epub 2005 Mar 24. PMID: 15790974; PMCID: PMC2715302.

[6] Gardner JM, Wildenberg SC, Keiper NM, Novak EK, Rusiniak ME, Swank RT, Puri N, Finger JN, Hagiwara N, Lehman AL, Gales TL, Bayer ME, King RA, Brilliant MH. The mouse pale ear (ep) mutation is the homologue of human Hermansky-Pudlak syndrome. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9238-43. doi: 10.1073/pnas.94.17.9238. PMID: 9256466; PMCID: PMC23134.

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