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. 2001 Nov;69(5):981-8.
doi: 10.1086/324340. Epub 2001 Sep 26.

Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4

J M Newton  1 , O Cohen-Barak, N Hagiwara, J M Gardner, M T Davisson, R A King, M H Brilliant
Affiliations

Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4

J M Newton et al. Am J Hum Genet. 2001 Nov.

Abstract

Oculocutaneous albinism (OCA) affects approximately 1/20,000 people worldwide. All forms of OCA exhibit generalized hypopigmentation. Reduced pigmentation during eye development results in misrouting of the optic nerves, nystagmus, alternating strabismus, and reduced visual acuity. Loss of pigmentation in the skin leads to an increased risk for skin cancer. Two common forms and one infrequent form of OCA have been described. OCA1 (MIM 203100) is associated with mutations of the TYR gene encoding tyrosinase (the rate-limiting enzyme in the production of melanin pigment) and accounts for approximately 40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for approximately 50% of OCA worldwide. OCA3 (MIM 203290), a rare form of OCA and also known as "rufous/red albinism," is associated with mutations in TYRP1 (encoding tyrosinase-related protein 1). Analysis of the TYR and P genes in patients with OCA suggests that other genes may be associated with OCA. We have identified the mouse underwhite gene (uw) and its human orthologue, which underlies a new form of human OCA, termed "OCA4." The encoded protein, MATP (for "membrane-associated transporter protein") is predicted to span the membrane 12 times and likely functions as a transporter.

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Figures

Figure 1
Figure 1
Mapping of mouse uw on proximal chromosome 15. F1 offspring generated from C57BL/6J-Uwdbr/Uwdbr X CAST/Ei-+/+ matings were intercrossed. We genotyped both +/+ and Uwdbr/Uwdbr F2 mice, for strain-specific alleles, with a panel of PCR markers, according to manufacturer’s protocols (Research Genetics). The physical map of D15Mit markers used in this cross is shown relative to mapped genes and is compared with the homologous region of human 5p. The gene order and spacing of human genes were deduced from data deposited in the Celera public database.
Figure 2
Figure 2
Conservation of human and mouse MATP proteins. Two-way clustal alignment of human and mouse MATP amino acid sequences is shown. Identical/similar residues are boxed; identical residues are shaded; predicted transmembrane domains are underlined. The position of the Uwdbr substitution is indicated by the asterisk (*), and the uwd substitution is indicated by the pound sign (#).
Figure 3
Figure 3
Similarity between topology of MATP protein and that of known transporters. Membrane topology was predicted on the basis of analyses by several programs, such as MacVector and the Web-based software TMHMM (v. 2.0) and TopPred 2. The sucrose-symporter signature sequence residues are indicated the asterisks (*). Residues altered by the Uwdbr and uwd mutations are also indicated.
Figure 4
Figure 4
Expression of the Matp gene in weanling eyes. For northern analysis, two identical blots containing 5 μg of total eye RNA from each of the strains indicated were hybridized with probes from either the mouse Matp cDNA (nucleotides 118–1004 [upper panel]) or the mouse p cDNA (nucleotides 375–2773 [lower panel]).
Figure 5
Figure 5
OCA4 caused by mutations in MATP, showing hypopigmentation of skin, hair, and eyes. Inset, Same patient as a child.
See this image and copyright information in PMC

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References

Electronic-Database Information

    1. Celera, http://www.celera.com/ (for human chromosome 5p sequences)
    1. GenBank, http://www.ncbi.nlm.nih.gov/GenBank/ (for mouse Matp cDNA from present study [accession number AY034377] and from Fukamachi et al. [2001] [accession number AF360357], human MATP cDNA [previously known as “AIM1” {accession number AF172849}], and medaka-fish MATP-b [accession number AF332510])
    1. Human Genome, The, http://www.ncbi.nlm.nih.gov/genome/guide/human/ (for human chromosome 5p sequences)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for OCA1 [MIM 203100], OCA2 [MIM 203200], and OCA3 [MIM 203290])
    1. TMHMM (v. 2.0), http://www.cbs.dtu.dk/services/TMHMM/ (for membrane-topology predictions)

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