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Previous Volume 330:529-534 February 24, 1994 Number 8 Next

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ABSTRACT

Background Type II (tyrosinase-positive) oculocutaneous albinism is an autosomal recessive disorder that has recently been mapped to chromosome segment 15q11-q13. The frequency of this disorder is greatly increased in patients with Prader-Willi or Angelman syndrome, both of which involve deletions of chromosome 15q. The P protein is a transmembrane polypeptide that may transport small molecules such as tyrosine, the precursor of melanin. The P gene is located in chromosome segment 15q11-q13.

Methods We studied the tyrosinase and P genes in three patients with type II oculocutaneous albinism, one of whom also had Prader-Willi syndrome, and in one patient with a milder syndrome known as autosomal recessive ocular albinism. Individual exons of these genes were amplified from the DNA of each patient by the polymerase chain reaction and screened for mutations by simultaneous analyses of single-stranded conformation polymorphisms and heteroduplexes and subsequent DNA sequencing.

Results Mutations of the P gene were identified in all four patients. These included one frame shift, three missense mutations that result in amino acid substitutions, and one mutation that affects RNA splicing. The patient with Prader-Willi syndrome plus albinism had a typical deletion of the paternal chromosome 15, rendering him hemizygous for a maternally inherited mutant allele of the P gene. The child with ocular albinism was heterozygous for two different mutations in the P gene.

Conclusions Abnormalities of the P gene are associated with a wide range of clinical phenotypes, including type II oculocutaneous albinism, albinism associated with the Prader-Willi syndrome, and at least some cases of autosomal recessive ocular albinism.

Recently, we identified the human P gene,⁶ which proved to correspond to the pink-eyed dilution (p) locus of the mouse,^6,7 which has a mutant phenotype similar to that of human type II oculocutaneous albinism. The P polypeptide appears to be an integral membrane protein with structural homology to transporters of amino acids, and we have speculated that the P protein might transport tyrosine, the precursor of melanin⁶. We identified a partial deletion of the P gene in a patient with the Prader-Willi syndrome plus type II oculocutaneous albinism,⁶ and we therefore suggested that mutations of the P gene may account for some or all forms of type II oculocutaneous albinism in humans. Here, we describe point mutations of the P gene in two patients with isolated type II (tyrosinase-positive) oculocutaneous albinism (Patients 1 and 2), a patient with both the Prader-Willi syndrome and albinism (Patient 3), and a patient with apparent autosomal recessive ocular albinism (Patient 4) (Figure 1). Together, our findings indicate that the spectrum of clinical phenotypes associated with mutations of the P gene in humans is exceedingly broad, resulting in at least three clinical entities previously thought to be distinct.

View larger version (4K): [in this window] [in a new window]   Figure 1. Locations of P Gene Mutations Associated with Albinism. The black box denotes the 838-amino-acid P polypeptide. Circles indicate missense substitutions at codons 443, 481, and 743; the diamond indicates a frame shift at codon 654; and the zigzag indicates a splice-junction mutation within the 17th intervening sequence, just distal to codon 614.

 
Case Reports

Patient 1

Patient 1 was an eight-year-old Pakistani girl with clinically severe type II oculocutaneous albinism, a member of a large and highly inbred kindred (Figure 2). Her skin was virtually white, with no apparent tanning ability, and her hair was pale golden yellow. Her irides were pale blue and showed transillumination, and the optic fundi appeared nonpigmented, with hypoplastic maculae. Visual acuity was decreased, and she had nystagmus. Her parents were first cousins and had normal pigmentation. She had one affected sister, three unaffected siblings, and an affected double first cousin. A qualitative assay of hair-bulb tyrosinase² failed to detect enzyme activity in the patient but showed normal activity in her similarly affected sister, findings indicative of the high rate of false negative results associated with this unreliable and thus not very useful test.

View larger version (10K): [in this window] [in a new window]   Figure 2. Pedigree of Patient 1 and Inheritance of a Frame-Shift Deletion at Codon 654 of the P Gene. The arrow indicates Patient 1. Solid symbols denote persons with type II oculocutaneous albinism, open symbols persons with normal pigmentation, circles female family members, and squares male family members. Double horizontal lines represent consanguineous matings. A plus sign indicates the presence of the frame shift at codon 654, and a minus sign its absence.

 
Patient 2

Patient 2 was a four-year-old boy of northern European ancestry who had typical type II oculocutaneous albinism. His skin was very lightly pigmented with no apparent tanning ability, and his hair was pale golden yellow. His irides were blue and showed transillumination, and the fundi appeared nonpigmented, with hypoplastic maculae. His corrected visual acuity was 20/100, and he had nystagmus and strabismus. A chromosomal analysis demonstrated mosaicism: 46,XY/46,XY,dup(15)(q12); the duplication occurred in 25 percent of stimulated peripheral-blood leukocytes. This duplication appears to constitute a nonpathologic chromosomal variant,⁸ and chromosomal analyses of the parents were not performed. Hair-bulb tyrosinase activity was normal. The parents were unrelated, and there was no family history of albinism.

Patient 3

Patient 3 was a seven-year-old boy of northern European ancestry who had typical type II oculocutaneous albinism and Prader-Willi syndrome. His albinotic phenotype was similar to that of Patient 2; findings of Prader-Willi syndrome included characteristic facial features, small hands and feet, small penis and testes, hypotonia, developmental delay, and hyperphagia and obesity. Chromosomal analysis demonstrated a deletion of 15q11.2-q13.1, whereas the karyotypes of his unrelated parents, who had normal pigmentation, were normal. Hair-bulb tyrosinase activity was normal. There was no family history of albinism, and the patient had no siblings.

Patient 4

Patient 4 was a seven-year-old girl of northern European ancestry who had apparent autosomal recessive ocular albinism. Her skin was fair and tanned normally, and her hair was reddish brown. Her irides were blue and showed transillumination, and the fundi appeared nonpigmented, with hypoplastic maculae. She had nystagmus and severe myopia; her corrected visual acuity was 20/200. Her parents were unrelated and had normal pigmentation, and there was no family history of albinism. Hair-bulb tyrosinase activity was normal.

Methods

Analyses of Single-Stranded Conformation Polymorphisms, Heteroduplexes, and DNA Sequences of P Gene Exon Segments

Genomic DNA was isolated from peripheral-blood leukocytes from the patients, selected family members, and unrelated normal control subjects. The five exons constituting the tyrosinase gene⁹ and the 24 coding exons of the human P gene plus adjacent noncoding sequences (unpublished data) were amplified from genomic DNA by the polymerase chain reaction (PCR)¹⁰. The amplified segments were then screened for mutations by simultaneous analyses of single-stranded conformation polymorphisms (SSCPs) and heteroduplexes¹¹. Exon segments that yielded aberrant patterns were independently reamplified from genomic DNA in duplicate and cloned in M13mp18, and the DNA sequences of at least six independent clones were determined¹².

Genetic Segregation and Linkage Analyses

Selected exon segments from the P gene were amplified by PCR from the genomic DNA of the patients, available relatives, and unrelated normal controls. The occurrence of specific mutant alleles in these subjects was tested by SSCP and heteroduplex analyses or by digestion of the PCR products with appropriate restriction enzymes and electrophoresis in 8 percent polyacrylamide gels (or by both methods in some instances). For the family of Patient 1, lod-score analysis was carried out with the 1987 version of the Liped program¹³.

Results

Heteroduplex and SSCP screening of the tyrosinase gene in Patient 1, who was the product of inbreeding and had clinically severe type II oculocutaneous albinism, demonstrated no abnormalities. However, screening of her P gene demonstrated an apparently homozygous abnormal pattern for exon 20. Except for a series of common, nonpathologic DNA-sequence polymorphisms that we have also observed among numerous normal persons, the other 23 exons of the P gene appeared to be normal. Exon 20 was therefore independently reamplified and cloned in M13mp18, and a DNA-sequence analysis of eight clones showed that all had a deletion of a single base at codon 654 (Figure 3). This deletion results in a frame shift, with a consequent truncation of the distal P nonsense polypeptide at codon 662.

View larger version (7K): [in this window] [in a new window]   Figure 3. DNA Sequences in the Region of the Frame-Shift Mutation at Codon 654 of the P Gene in Patient 1. The sequence of the coding strand is shown. The frame-shift deletion of one base at codon 654 is indicated. Exon 20 sequences and the terminal part of the 19th intervening sequence (IVS19) are shown.

 
The frame-shift deletion at codon 654 creates a novel cleavage site for HinfI (GANTC), permitting us both to confirm the mutation in Patient 1 and to analyze the segregation of this mutant allele in her family. We screened a total of 7 unaffected members and 1 affected member of her family (Figure 2) and 14 unrelated Indo-Pakistani controls by both HinfI cleavage and SSCP and heteroduplex analyses of their exon 20 PCR products. Patient 1 and her similarly affected double first cousin were both homozygous for the frame shift at codon 654, and a number of unaffected relatives were heterozygous (Figure 2). In contrast, this mutation was absent in all the unrelated controls. The findings of two-point genetic linkage analysis were consistent with linkage between the frame shift and type II oculocutaneous albinism in this family (lod score of 2.70 at a recombination fraction of 0).

Heteroduplex and SSCP screening of the P gene in Patient 2, who had typical type II oculocutaneous albinism, demonstrated apparent abnormalities of exons 13 and 22; the other 22 P exons and all 5 exons of the tyrosinase gene appeared to be normal. DNA-sequence analysis of exons 13 and 22 of the P gene demonstrated that Patient 2 was heterozygous for two different missense substitutions. As shown in Figure 4, the abnormality in exon 13 was at codon 443: isoleucine (ATC) was substituted for valine (GTC) (Val443Ile). The abnormality in exon 22 was at codon 743: leucine (CTG) was substituted for proline (CCG) (Pro743Leu). The Val443Ile mutation abolishes a restriction site for MaeIII (GTNAC), permitting us to confirm the mutation in the exon 13 PCR product that was independently amplified from the patient's DNA; the Pro743Leu mutation does not alter any known restriction site. Heteroduplex and SSCP screening of the PCR products of exons 13 and 22 amplified from the DNA of 51 unrelated normal white subjects revealed only the normal patterns, indicating that neither the Val443Ile nor the Pro743Leu substitution is a common polymorphism.

View larger version (10K): [in this window] [in a new window]   Figure 4. DNA Sequences in the Region of the Valine-to-Isoleucine Missense Mutation at Codon 443 and the Proline-to-Leucine Missense Mutation at Codon 743 of the P Gene in Patient 2. The Val443Ile mutation was also observed in Patient 3.

 
To determine whether the Val443Ile and Pro743Leu substitutions occur on the same chromosome or on different chromosomes in Patient 2, we performed MaeIII cleavage and SSCP and heteroduplex analyses, respectively, of the exon 13 and exon 22 PCR products amplified from DNA from the patient's parents. These analyses demonstrated that Patient 2 inherited the Val443Ile mutation from his father and the Pro743Leu mutation from his mother. Thus, he is a compound heterozygote for these two missense mutant alleles of the P gene.

Cytogenetic analyses in Patient 3, who had type II oculocutaneous albinism and Prader-Willi syndrome, demonstrated a typical spontaneous deletion of chromosome segment 15q11-q13¹⁴. Since the human P gene is located within this chromosomal region,^6,15 Patient 3 is hemizygous for the P gene. All 24 exons of the P gene were successfully amplified from the patient's DNA, indicating that the remaining allele is structurally intact. However, SSCP and heteroduplex screening demonstrated an abnormal pattern for exon 13 that appeared to be identical to one of the abnormal alleles of Patient 2. The other 23 exons of the P gene and all 5 exons of the tyrosinase gene appeared to be normal, although only single-allele patterns of the P gene polymorphisms were visualized, a finding consistent with hemizygosity for the P gene. Exon 13 of the P gene was independently reamplified and cloned in M13mp18, and DNA-sequence analyses of all the clones demonstrated the same missense substitution -- that of Val443Ile -- that we identified in Patient 2 (Figure 4).

To ascertain the parental origins of both the chromosome 15 deletion and the Val443Ile mutation in Patient 3, we carried out SSCP, heteroduplex, and MaeIII cleavage analyses of the exon 13 PCR product amplified from genomic DNA from both his parents. As shown in Figure 5, even though the patient had no normal P gene allele (lane 2), exon 13 of the P gene appeared to be normal in his father (lane 3). In contrast, his mother was heterozygous for the Val443Ile mutation (lane 4). Thus, Patient 3 has a spontaneous deletion of the paternal chromosome 15, accounting for the Prader-Willi phenotype, and he is hemizygous for a mutant allele of the P gene containing the Val443Ile substitution inherited from his mother, accounting for the phenotype of type II oculocutaneous albinism.

View larger version (25K): [in this window] [in a new window]   Figure 5. Inheritance of the Val443Ile Mutation in the Family of Patient 3. The Val443Ile mutation abolishes a cleavage site for MaeIII. Segments of exon 13 of the P gene were amplified by PCR from DNA of a normal subject (lane 1), Patient 3 (lane 2), and his father (lane 3) and mother (lane 4), cleaved with MaeIII, and analyzed by polyacrylamide-gel electrophoresis. The normal PCR product is cleaved by MaeIII into three fragments of 150, 54, and 27 base pairs (bp). The PCR product amplified from the allele containing the Val443Ile mutation is cleaved into two fragments of 177 and 54 bp. M denotes the molecular size standards, a mixture of BstNI and HaeIII digests of plasmid pBR322. The half-solid symbol indicates that the patient's mother is heterozygous for the Val443Ile mutant allele.

 
Heteroduplex and SSCP screening of the P gene in Patient 4, who had apparent ocular albinism, showed abnormalities of exons 14 and 17; the other 22 P gene exons and all exons of the tyrosinase gene appeared to be normal. DNA-sequence analyses showed that Patient 4 was heterozygous for two different mutations. As shown in Figure 6, the abnormality in exon 17 was a substitution of thymine for guanine at the first base of the 17th intervening sequence (IVS17), abolishing the universal guanine-thymine dinucleotide that constitutes the 5' splice junction, a sequence element required for normal RNA splicing. The upstream exon 17 sequence and the downstream IVS17 sequence contain no potential in-frame cryptic splice sites, so the skipping of exon 17 would result in a frame shift. This mutation is thus expected to eliminate the expression of normal P gene messenger RNA and the P polypeptide from this allele. The abnormality in exon 14 was a missense substitution at codon 481: threonine (ACC) was substituted for alanine (GCC) (Ala481Thr).

View larger version (8K): [in this window] [in a new window]   Figure 6. DNA Sequences in the Region of the IVS17 Splice-Junction Mutation and the Alanine-to-Threonine Missense Mutation at Codon 481 of the P Gene in Patient 4.

 
The position 1 mutation at IVS17 abolishes a KpnI restriction site (GGTACC), and the Ala481Thr mutation abolishes a Fnu4HI restriction site (GCNGC), permitting us to confirm both mutations in the patient's DNA. Heteroduplex, SSCP, and Fnu4HI or KpnI cleavage analyses of the exon 14 and exon 17 PCR products amplified from her parents' DNA demonstrated that Patient 4 inherited the IVS17 splice-junction mutation from her father and the Ala481Thr mutation from her mother. Patient 4 is thus a compound heterozygote for these two mutant alleles of the P gene.

Surprisingly, SSCP and heteroduplex screening of the exon 14 PCR product amplified from 50 unrelated normal white subjects indicated that one of these subjects was heterozygous for the Ala481Thr mutant allele. Fnu4HI cleavage analysis confirmed that this allele contained the Ala481Thr substitution. Thus, the Ala481Thr substitution appears to be a relatively common mutant allele of the P gene (q = 0.01; 95 percent confidence interval, 0 to 0.055), most likely associated with a moderate reduction of P polypeptide function.

Discussion

The human P protein is an 838-amino-acid polypeptide that contains 12 putative transmembrane domains and exhibits structural homology to transporters of small organic molecules⁶. The P gene is located in chromosome segment 15q11-q13,^6,15 and type II (tyrosinase-positive) oculocutaneous albinism was recently mapped to this region by means of genetic linkage¹⁶. Our results provide evidence that point mutations of the P gene are associated with a wide range of clinical manifestations.

Patient 1 had clinically severe type II oculocutaneous albinism; her symptoms were nearly as severe as those of classic type IA (tyrosinase-negative) oculocutaneous albinism. This degree of severity was especially striking in that the patient was Pakistani and thus might be expected to have relatively more pigment than a person of northern European ancestry with an equivalent genotype. She was homozygous for a frame shift at codon 654 that results in a truncated and most likely completely nonfunctional P polypeptide. The lack of P polypeptide function in this patient is thus associated with relatively severe type II albinism.

Patients 2 and 3 both had symptoms that were more typical of the characteristics of type II oculocutaneous albinism in whites. Patient 2 was a compound heterozygote for two different allelic single-base missense substitutions of the P gene, Val443Ile and Pro743Leu. Patient 3 also had Prader-Willi syndrome, the result of a spontaneous cytogenetic deletion of 15q11.2- q13.1 on his paternally inherited chromosome. This rendered him hemizygous for the same Val443Ile substitution present in Patient 2, which was inherited from his mother. Both Val443 and Pro743 are located within portions of the P polypeptide that have been completely conserved between humans and mice,^6,7 and we did not detect either the Val443Ile or the Pro743Leu substitution as polymorphisms among normal subjects. Thus, both these substitutions are probably deleterious to P polypeptide function.

Patient 4 had a much milder clinical syndrome, characteristic of autosomal recessive ocular albinism. Her eyes appeared albinotic, whereas pigmentation of her skin and hair was entirely normal, although she was perhaps slightly fairer than her parents. She was also a compound heterozygote for two different mutant alleles of the P gene. One allele contained a mutation that destroys the 5' splice site of IVS17, which would presumably eliminate the expression of P polypeptide by this allele. The other allele contained a missense substitution, Ala481Thr. Ala481 is located near the center of a segment of the P gene that has been completely conserved between humans and mice, and the Ala481Thr substitution most likely results in moderately reduced function or stability of the P polypeptide. The Ala481Thr mutant allele appears to be relatively common (q 0.01), although homozygosity for this allele would be rare (approximately 1 person in 10,000). Persons who are compound heterozygotes for the Ala481Thr allele and a different mutant allele of the P gene resulting in little or no residual function, such as that containing the IVS17 splice-junction mutation, might not produce sufficient pigment during early embryogenesis for the normal development of the optic tract and would thus have ocular albinism.

Our results delineate the molecular basis of type II oculocutaneous albinism and provide the basis for the molecular diagnosis of this disorder. The range of clinical manifestations of this syndrome is quite broad and appears to include at least some cases of autosomal recessive ocular albinism, although this entity may ultimately prove heterogeneous in origin¹⁷. Abnormalities of the P gene also appear to account for hypopigmentation as one component of the Prader-Willi and Angelman syndromes, which result from deletions of chromosome segment 15q11-q13^14,15. Approximately 1 percent of patients with Prader-Willi or Angelman syndrome also have type II oculocutaneous albinism (as did Patient 3), the result of hemizygosity for inherited mutant alleles of the P gene⁶. Many more of these patients, however, have milder hypopigmentation,¹⁸ and some or all may be hemizygous for nonpathologic polymorphisms of the P polypeptide that only slightly reduce its function. Thus, various combinations of abnormalities of this one gene, P, underlie hypopigmentation as part of three seemingly distinct clinical entities. We can even speculate that nonpathologic but functionally important polymorphisms of the P gene may account for a considerable fraction of the normal variation in pigmentation.

It has been difficult to distinguish between the various forms of oculocutaneous albinism, especially in children, both because of clinical overlap and because of the unreliability of the hair-bulb tyrosinase assay. The availability of an accurate and early molecular approach to the diagnosis of type I and type II oculocutaneous albinism should allow us to provide more accurate prognostic information and genetic counseling to families at risk for these two important genetic disorders of pigmentation.

Supported by a Postdoctoral Grant (997, to Dr. Lee) and a Clinical Research Grant (6-408, to Dr. Spritz) from the March of Dimes Birth Defects Foundation, and by a grant (AR-39892, to Dr. Spritz) from the National Institutes of Health. Dr. Nicholls is a Pew Scholar in Biomedical Sciences.

Source Information

From the Departments of Medical Genetics (S.-T.L., R.L., R.A.S.) and Pediatrics (R.L., R.A.S.), University of Wisconsin, Madison; the Department of Genetics, Case Western Reserve University School of Medicine, Cleveland (R.D.N.); the Department of Pediatrics and Child Health, University of Birmingham, Birmingham Maternity Hospital, Edgbaston, Birmingham, United Kingdom (S.B.); and the Department of Ophthalmology, Hospital for Sick Children, Toronto (M.M.).

Address reprint requests to Dr. Spritz at 317 Laboratory of Genetics, 445 Henry Mall, University of Wisconsin, Madison, WI 53706.

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