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Oculocutaneous albinism type 2 with a P gene missense mutation in a patient with Angelman syndrome
  1. * Department of Paediatrics, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan
  2. Department of Dermatology, Osaka City University Medical School, Osaka, Japan
  3. Department of Paediatric Neurology, Fukuoka Children's Hospital Medical Centre, Fukuoka, Japan
  1. Dr Saitoh, ss11{at}

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Editor—Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive disorder characterised by defective melanin production of the skin, hair, and eyes,1 which is caused by mutations of the P gene.2 3The specific function of P has not been clarified, although it is likely to act as a transporter in the melanosomal membrane.2 4

The P gene is located in 15q11-q13, which is deleted in the majority of patients with Angelman syndrome (AS) and Prader-Willi syndrome (PWS).2 5 TheP gene is not imprinted and both alleles are expressed. PWS and AS patients with typical deletions are thus hemizygous for P. It is also well established that AS and PWS deletion patients usually show hypopigmentation of the skin and hair, and Pis suggested to be responsible for this hypopigmentation as well,6 7 although the mechanism has not yet been established.

A small intragenic deletion and a V443I missense mutation of theP gene were identified in the maternally inherited alleles of two PWS plus OCA2 patients who had a paternally inherited deletion of 15q11-q13.2 3 Here we describe the first evidence that a P gene mutation is responsible for OCA2 associated with AS.

The male patient was born at 38 weeks' gestation to unrelated Japanese parents. There were no complications of pregnancy or delivery, but the birth weight, 1850 g, was small for gestational dates. Generalised albinism was noted at birth. Motor development was delayed, and he had a generalised tonic-clonic convulsion at the age of 18 months. He was admitted to hospital at the age of 19 months because of non-convulsive epileptic status, as reported previously.8 Physical examination showed the typical facies of AS, including prominent mandible, protruding tongue, and relatively small head circumference (−1.72 SD). His skin and hair pigmentation was markedly reduced consistent with albinism (fig 1A). His hair colour was fair-blonde. Ophthalmological examination showed reduced pigmentation of the iris and a tigroid appearance of the retina with mildly reduced pigmentation. There was no nystagmus or other visual problems. He began walking unassisted at the age of 9 years with an ataxic gait typical of AS with the “hands up” position. He had severe mental retardation and could not speak. His skin, hair, and eye pigmentation gradually increased and he had dark hair by 12 years of age (fig 1B). His father and brother showed mild hypopigmentation of the skin and hair compared with other family members.

Figure 1

Phenotypic appearance of the patient at (A) 2 years of age and (B) 12 years of age.

High resolution chromosome analysis and fluorescence in situ hybridisation (FISH) using D15S10 (Vysis, Downers Grove, Illinois) as probe showed a karyotype 46,XY,del(15)(q11q13) in the patient. Parental origin of the deletion was studied by the DNA methylation test usingSNRPN exon 1 as probe.9 Genomic DNA was extracted from the patient and parents by a standard procedure.9 The SNRPN DNA methylation test indicated that the patient had only a paternal methylation pattern, indicating a maternal origin of the deletion (data not shown). These molecular cytogenetic results confirmed the clinical diagnosis of AS.

To screen for a P gene mutation, all 25 exons and flanking introns of the P gene were amplified by polymerase chain reaction (PCR) using the primers described by Lee et al,4agarose gel purified with GFX PCR and Gel Band Purification Kit (Amersham Pharmacia Biotech, Uppsala, Sweden), and direct sequenced with the ABI PRISM BigDye Terminator Cycle Sequencing Ready Reaction Kit. Sequence reactions were run on a Perkin-Elmer 310 Automatic Sequencer and analysed by use of LASERGENE software (DNASTAR, Madison, WI). A missense mutation A481T (1441G>A) as well as non-pathological polymorphisms (IVS11-4A>G, G780G (2340C>T), S788S (2364G>A)) of theP gene were identified in the patient (fig2). The 1441G>A mutation is located in exon 14 ofP and causes amino acid substitution of alanine for threonine at codon 481. The non-pathological polymorphisms have been previously described in other people.4 No wild type sequence was identified at these positions in the patient, as expected with hemizygosity at this locus. The father was shown to be heterozygous for the A481T mutation, whereas the mother was homozygous for the wild type allele (fig 2).

Figure 2

Segregation of the missense mutation in the patient and parents. The arrow indicates the position of the base substitution. The number below the arrow (1441) indicates the corresponding cDNA nucleotide position adapted from Lee et al.4

In this study the AS patient with OCA2 was shown to have a typical large deletion on the maternally inherited chromosome 15q, and a missense P mutation (A481T) on the paternally inherited chromosome. Most AS and PWS deletions are of similar size and P is always deleted in these patients.5 Since the patient has only the A481T mutation allele, the mother is homozygous for the normal allele, and the father is heterozygous for the A481T mutation allele and the normal allele, the maternally inherited P allele must be deleted in the patient. This was confirmed for the deletion origin by methylation analysis with the adjacent imprinted region of 15q11-q13.

AS patients with the common 15q deletion are frequently associated with hypopigmentation, whereas other classes of AS patients are less often hypopigmented.10 11 Similarly, hypopigmentation in PWS also correlates withP deletion.7 A hemizygous deletion of P cannot completely explain the mild degree of hypopigmentation more commonly seen in AS or PWS because heterozygous carriers of severe autosomal recessive OCA2 patients do not usually have hypopigmentation. Therefore, one can speculate that a pigmentation modifier gene(s) may be present in the deleted region of 15q11-q13.

The A481T mutation has previously been found in an African-American patient with P related autosomal recessive ocular albinism,3 as well as in one of 50 unrelated controls.4 The frequency of OCA2 is approximately 1/40 000 and 1/10 000 in whites and in African-Americans, respectively.1 12 Carrier frequency is thus estimated to be 1/50-1/100. The carrier frequency of A481T reported by Leeet al 4 may have been overestimated, since previous studies have not shown that A481T is a predominant mutation in OCA2.3 12 13

The function of the A481T allele was shown by transfecting A481T mutantP cDNA into pnull mouse melanocytes,14 which showed that the A481T allele had approximately 70% function of the wild type allele. Therefore, since our patient is hemizygous, he may only have 35% ofP gene function in melanin production compared with the wild type.

Our patient showed a severe deficiency of pigmentation during infancy to early childhood, but melanin production gradually increased and he had dark hair by 12 years of age. This is in keeping with the natural history of OCA2, as gradual increase in pigmentation during childhood is commonly seen in OCA2 patients. These findings are also consistent with the finding that the A481T allele has the potential for producing significant amounts of melanin as shown in the tissue culture experiments. Many mammalian genes are known to have an effect on pigmentation15 and are developmentally controlled, although the precise mechanisms have not been established. Possible deletion of other pigmentation modifier gene(s) located in 15q may also explain the profound hypopigmentation in our patient during early childhood.

In conclusion, we describe the first genetic evidence that theP gene mutation is responsible for OCA2 associated with AS. These findings increase the spectrum of clinical conditions (AS or PWS plus OCA2, OCA2, ocular albinism) associated withP gene mutations.


The authors thank Drs K Kobayashi, R D Nicholls, and R A Spritz for critical comments on the manuscript. This work was supported by the Research Grant (8A-8) for Nervous and Mental Disorders from the Ministry of Health and Welfare of Japan (SS), by grant in aid No 09470190 from the Ministry of Education, Science and Culture of Japan (KF), and by the Mochida Memorial Foundation for Medical and Pharmaceutical Research (KF).