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Retinal Dystrophy Due to Paternal Isodisomy for Chromosome 1 or Chromosome 2, with Homoallelism for Mutations in RPE65 or MERTK, Respectively

2002; Elsevier BV; Volume: 70; Issue: 1 Linguagem: Inglês

10.1086/338455

1537-6605

Debra A. Thompson, Christina L. McHenry, Yun Li, Julia E. Richards, Mohammad Othman, E. Schwinger, Douglas Vollrath, Samuel G. Jacobson, Andreas Gal,

Retinal Development and Disorders

Uniparental disomy (UPD) is a rare condition in which a diploid offspring carries a chromosomal pair from a single parent. We now report the first two cases of UPD resulting in retinal degeneration. We identified an apparently homozygous loss-of-function mutation of RPE65 (1p31) in one retinal dystrophy patient and an apparently homozygous loss-of-function mutation of MERTK (2q14.1) in a second retinal dystrophy patient. In both families, the gene defect was present in the patient's heterozygous father but not in the patient's mother. Analysis of haplotypes in each nuclear kindred, by use of DNA polymorphisms distributed along both chromosomal arms, indicated the absence of the maternal allele for all informative markers tested on chromosome 1 in the first patient and on chromosome 2 in the second patient. Our results suggest that retinal degeneration in these individuals is due to apparently complete paternal isodisomy involving reduction to homoallelism for RPE65 or MERTK loss-of-function alleles. Our findings provide evidence for the first time, in the case of chromosome 2, and confirm previous observations, in the case of chromosome 1, that there are no paternally imprinted genes on chromosomes 1 and 2 that have a major effect on phenotype. Uniparental disomy (UPD) is a rare condition in which a diploid offspring carries a chromosomal pair from a single parent. We now report the first two cases of UPD resulting in retinal degeneration. We identified an apparently homozygous loss-of-function mutation of RPE65 (1p31) in one retinal dystrophy patient and an apparently homozygous loss-of-function mutation of MERTK (2q14.1) in a second retinal dystrophy patient. In both families, the gene defect was present in the patient's heterozygous father but not in the patient's mother. Analysis of haplotypes in each nuclear kindred, by use of DNA polymorphisms distributed along both chromosomal arms, indicated the absence of the maternal allele for all informative markers tested on chromosome 1 in the first patient and on chromosome 2 in the second patient. Our results suggest that retinal degeneration in these individuals is due to apparently complete paternal isodisomy involving reduction to homoallelism for RPE65 or MERTK loss-of-function alleles. Our findings provide evidence for the first time, in the case of chromosome 2, and confirm previous observations, in the case of chromosome 1, that there are no paternally imprinted genes on chromosomes 1 and 2 that have a major effect on phenotype. Uniparental disomy (UPD) arises when a diploid individual carries both homologs of a chromosomal pair from a single parent (uniparental heterodisomy) or two copies of a single parental chromosome (uniparental isodisomy) (Engel Engel, 1980Engel E A new genetic concept: uniparental disomy and its potential effect, isodisomy.Am J Med Genet. 1980; 6: 137-143Crossref PubMed Scopus (379) Google Scholar). Uniparental heterodisomy occurs most frequently in cases in which both homologs are maternally derived (maternal UPD), and uniparental isodisomy occurs most frequently in cases in which both homologs are paternally derived (paternal UPD), with the overall prevalence of maternal UPD being three times greater than that of paternal UPD (Kotzot Kotzot, 1999Kotzot D Abnormal phenotypes in uniparental disomy uniparental disomy: Fundamental aspects and a critical review with bibliography of uniparental disomy other than 15.Am J Med Genet. 1999; 82: 265-274Crossref PubMed Scopus (121) Google Scholar). Possible mechanisms of UPD include gamete complementation, trisomic zygote rescue (reduction to disomy), postzygotic monosomy duplication, and somatic crossing-over (Engel and DeLozier-Blanchet Engel and DeLozier-Blanchet, 1991Engel E DeLozier-Blanchet CD Uniparental disomy, isodisomy, and imprinting: probable effects in man and strategies for their detection.Am J Med Genet. 1991; 40: 432-439Crossref PubMed Scopus (93) Google Scholar; Robinson Robinson, 2000Robinson WP Mechanisms leading to uniparental disomy and their clinical consequences.Bioessays. 2000; 22: 452-459Crossref PubMed Scopus (243) Google Scholar). Disease phenotypes associated with UPD can be due to trisomy mosaicism, unmasking of autosomal recessive gene defects by reduction to homoallelism, or imprinting (Engel Engel, 1998Engel E Uniparental disomies in unselected populations.Am J Hum Genet. 1998; 63: 962-966Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar; Kotzot Kotzot, 1999Kotzot D Abnormal phenotypes in uniparental disomy uniparental disomy: Fundamental aspects and a critical review with bibliography of uniparental disomy other than 15.Am J Med Genet. 1999; 82: 265-274Crossref PubMed Scopus (121) Google Scholar). Studies of UPD in humans and mice played an important part in establishment of the role that imprinting plays in parent-of-origin–specific gene expression and in identification of imprinted regions of the genome that have profound effects on fetal growth, development, and viability (Preece and Moore Preece and Moore, 2000Preece MA Moore GE Genomic imprinting, uniparental disomy and foetal growth.Trends Endocrinol Metab. 2000; 11: 270-275Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Studies of autosomal recessive disorders identified a number of cases of UPD resulting in reduction to homoallelism of disease-associated mutations (Engel Engel, 1998Engel E Uniparental disomies in unselected populations.Am J Hum Genet. 1998; 63: 962-966Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Inherited retinal dystrophies are a genetically heterogeneous group of diseases responsible for visual deficits that vary in severity and age at onset and include some forms of congenital blindness. Mutations in a number of genes expressed in the photoreceptor cells or the adjacent retinal pigment epithelium (RPE) have been shown to cause autosomal dominant and recessive forms of retinal degeneration (Phelan and Bok Phelan and Bok, 2000Phelan JK Bok D A brief review of retinitis pigmentosa and the identified retinitis pigmentosa genes.Mol Vis. 2000; 6: 116-124PubMed Google Scholar). Our previous studies identified two disease genes, RPE65 and MERTK, involved in essential aspects of RPE physiology necessary for photoreceptor-cell function and viability (Gu et al. Gu et al., 1997Gu S-M Thompson DA Srikumari CRS Lorenz B Finckh U Nicoletti A Murthy KR Rathmann M Kumaramanickavel G Denton MJ Gal A Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy.Nat Genet. 1997; 17: 194-197Crossref PubMed Scopus (500) Google Scholar; Gal et al. Gal et al., 2000Gal A Li Y Thompson DA Weir J Orth U Jacobson SG Apfelstedt-Sylla E Vollrath D Mutations in MERTK, the human ortholog of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.Nat Genet. 2000; 26: 270-271Crossref PubMed Scopus (507) Google Scholar). RPE65 (MIM 180069) encodes a unique protein localized in the RPE smooth endoplasmic reticulum and is required for the conversion of vitamin A to 11-cis retinal, the chromophore of the visual pigments (Hamel et al. Hamel et al., 1993Hamel CP Tsilou E Pfeffer BA Hooks JJ Detrick B Redmond TM Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro.J Biol Chem. 1993; 268: 15751-15757Abstract Full Text PDF PubMed Google Scholar; Nicoletti et al. Nicoletti et al., 1995Nicoletti A Wong DJ Kawase K Gibson LH Yang-Feng TL Richards JE Thompson DA Molecular characterization of the human gene encoding an abundant 61 kDa protein specific to the retinal pigment epithelium.Hum Mol Genet. 1995; 4: 641-649Crossref PubMed Scopus (100) Google Scholar; Redmond et al. Redmond et al., 1998Redmond TM Yu S Lee E Bok D Hamasaki D Chen N Goletz P Ma JX Crouch RK Pfeifer K Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle.Nat Genet. 1998; 20: 344-351Crossref PubMed Scopus (746) Google Scholar). Mutations in RPE65 cause early-onset severe retinal degeneration that is often diagnosed as Leber congenital amaurosis (Gu et al. Gu et al., 1997Gu S-M Thompson DA Srikumari CRS Lorenz B Finckh U Nicoletti A Murthy KR Rathmann M Kumaramanickavel G Denton MJ Gal A Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy.Nat Genet. 1997; 17: 194-197Crossref PubMed Scopus (500) Google Scholar; Marlhens et al. Marlhens et al., 1997Marlhens F Bareil C Griffoin JM Zrenner E Amalric P Eliaou C Liu SY Harris E Redmond TM Arnaud B Claustres M Hamel CP Mutations in RPE65 cause Leber's congenital amaurosis.Nat Genet. 1997; 17: 139-141Crossref PubMed Scopus (487) Google Scholar). Over 50 different disease-associated mutations have been reported, with current estimates indicating that RPE65 mutations are responsible for ∼10% of cases of autosomal recessive retinal dystrophy with early onset and severe phenotype (Thompson et al. Thompson et al., 2000Thompson DA Gyürüs P Fleischer L Bingham EL McHenry CL Apfelstedt-Sylla E Zrenner E Lorenz B Richards JE Jacobson SG Sieving PA Gal A Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration.Invest Ophthalmol Vis Sci. 2000; 41: 4293-4299PubMed Google Scholar). MERTK (MIM 604705) encodes a tyrosine kinase receptor that is the human ortholog of the Royal College of Surgeons (RCS) rat retinal-dystrophy gene (D'Cruz et al. D'Cruz et al., 2000D'Cruz PM Yasumura D Weir J Matthes MT Abderrahim H LaVail MM Vollrath D Mutation of the receptor tyrosine kinase Mertk in the retinal dystrophic RCS rat.Hum Mol Genet. 2000; 9: 645-652Crossref PubMed Scopus (684) Google Scholar). In the RCS rat, mutations in Mertk cause retinal degeneration as a result of defective phagocytosis of shed photoreceptor outer segments by the RPE (Mullen and LaVail Mullen and LaVail, 1976Mullen RJ LaVail MM Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimeras.Science. 1976; 192: 799-801Crossref PubMed Scopus (417) Google Scholar; Edwards and Szamier Edwards and Szamier, 1977Edwards RB Szamier RB Defective phagocytosis of isolated rod outer segments by RCS rat retinal pigment epithelium in culture.Science. 1977; 197: 1001-1003Crossref PubMed Scopus (204) Google Scholar). Disease-associated mutations of MERTK have been reported in patients with autosomal recessive retinitis pigmentosa (Gal et al. Gal et al., 2000Gal A Li Y Thompson DA Weir J Orth U Jacobson SG Apfelstedt-Sylla E Vollrath D Mutations in MERTK, the human ortholog of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.Nat Genet. 2000; 26: 270-271Crossref PubMed Scopus (507) Google Scholar). We identified two families in which a mutation of RPE65 or MERTK, present in apparently homozygous form in the affected individual, was carried in heterozygous form by only one parent (Gal et al. Gal et al., 2000Gal A Li Y Thompson DA Weir J Orth U Jacobson SG Apfelstedt-Sylla E Vollrath D Mutations in MERTK, the human ortholog of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.Nat Genet. 2000; 26: 270-271Crossref PubMed Scopus (507) Google Scholar; Thompson et al. Thompson et al., 2000Thompson DA Gyürüs P Fleischer L Bingham EL McHenry CL Apfelstedt-Sylla E Zrenner E Lorenz B Richards JE Jacobson SG Sieving PA Gal A Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration.Invest Ophthalmol Vis Sci. 2000; 41: 4293-4299PubMed Google Scholar). In the first case (patient 1723), a 51-year-old man diagnosed with Leber congenital amaurosis in childhood had an apparently homozygous mutation of RPE65, IVS1+5g→a, that is the most frequently occurring mutation in this gene (comprising ∼19% of all reported RPE65 disease alleles) (Thompson et al. Thompson et al., 2000Thompson DA Gyürüs P Fleischer L Bingham EL McHenry CL Apfelstedt-Sylla E Zrenner E Lorenz B Richards JE Jacobson SG Sieving PA Gal A Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration.Invest Ophthalmol Vis Sci. 2000; 41: 4293-4299PubMed Google Scholar). The mutation identified in patient 1723 was present in heterozygous form in his unaffected father and brother but was not present in his mother. Evidence suggesting that no maternal RPE65 allele was transmitted to the patient was obtained by analysis of two intragenic DNA polymorphisms; a microsatellite repeat (D1S2803) in the promoter region (Nicoletti et al. Nicoletti et al., 1998Nicoletti A Kawase K Thompson DA Promoter analysis of RPE65, the gene encoding a 61-kDa retinal pigment epithelium-specific protein.Invest Ophthalmol Vis Sci. 1998; 39: 637-644PubMed Google Scholar) and an intronic single-nucleotide polymorphism (IVS6+22c→t). The patient appeared to be homozygous for both markers, and only the paternal allele was detected (fig. 1). Further analysis of 19 informative microsatellite markers, spread out along both arms of chromosome 1, suggested complete absence of the maternal homolog, since the patient appeared homozygous for the paternal allele in each case. Genotypes obtained for 12 other partially informative DNA polymorphisms on chromosome 1, including an intragenic 2-bp insertion/deletion–type polymorphism (2383ins/del) located in the 3′ UTR of RPE65 (Nicoletti et al. Nicoletti et al., 1995Nicoletti A Wong DJ Kawase K Gibson LH Yang-Feng TL Richards JE Thompson DA Molecular characterization of the human gene encoding an abundant 61 kDa protein specific to the retinal pigment epithelium.Hum Mol Genet. 1995; 4: 641-649Crossref PubMed Scopus (100) Google Scholar), were also consistent with the assumption of paternal isodisomy of chromosome 1. The assumed biological relationship of the patient to his parents was confirmed by analysis of a number of microsatellite markers on chromosomes 2, 3, 6, and X (data not shown). Routine cytogenetic analysis of metaphase spreads prepared from peripheral blood showed a normal male karyotype, 46,XY. Patient 1723 has no obvious physical abnormalities and is currently engaged in a high-level professional career. He was born after a full-term pregnancy, when his mother and father were 22 and 25 years of age, respectively. The patient has hyperbetalipoproteinemia, which is also present in his father and in his father's siblings, as well as benign hyperbilirubinemia (Gilbert syndrome). Neither condition can be ascribed to the patient's UPD status. Onset of his retinal disease occurred at age <5 years, with severe visual loss and nystagmus. At age 8 years, his visual acuity was 20/200, with a refraction of +4.00. Signals on rod and cone electroretinograms were not detectable. At age 50 years, he had only small islands of vision remaining. The course and severity of the patient's visual disorder fit well within the range of clinical phenotypes exhibited by other reported patients with retinal dystrophy who had mutations of RPE65 (Gu et al. Gu et al., 1997Gu S-M Thompson DA Srikumari CRS Lorenz B Finckh U Nicoletti A Murthy KR Rathmann M Kumaramanickavel G Denton MJ Gal A Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy.Nat Genet. 1997; 17: 194-197Crossref PubMed Scopus (500) Google Scholar; Marlhens et al. Marlhens et al., 1997Marlhens F Bareil C Griffoin JM Zrenner E Amalric P Eliaou C Liu SY Harris E Redmond TM Arnaud B Claustres M Hamel CP Mutations in RPE65 cause Leber's congenital amaurosis.Nat Genet. 1997; 17: 139-141Crossref PubMed Scopus (487) Google Scholar; Morimura et al. Morimura et al., 1998Morimura H Fishman GA Grover SA Fulton AB Berson EL Dryja TP Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis.Proc Natl Acad Sci USA. 1998; 95: 3088-3093Crossref PubMed Scopus (368) Google Scholar; Perrault et al. Perrault et al., 1999Perrault I Rozet J-M Ghazi I Leowski C Bonnemaison M Geber S Ducroq D Cabot A Souied E Dufier J-L Munnich A Kaplan J Different functional outcome of RetGC1 and RPE65 gene mutations in Leber congenital amaurosis.Am J Hum Genet. 1999; 64: 1225-1228Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar; Lorenz et al. Lorenz et al., 2000Lorenz B Gyurus P Preising M Bremser D Gu S Andrassi M Gerth C Gal A Early-onset, severe, rod-cone dystrophy in young children with RPE65 mutations.Invest Ophthalmol Vis Sci. 2000; 41: 2735-2742PubMed Google Scholar; Lotery et al. Lotery et al., 2000Lotery AJ Namperumalsamy P Jacobson SG Weleber RG Fishman GA Musarella MA Hoyt CS Héon E Levin A Jan J Lam B Carr RE Franklin A Radha S Andorf JL Sheffield VC Stone EM Mutation analysis of 3 genes in patients with Leber congenital amaurosis.Arch Ophthalmol. 2000; 118: 538-543Crossref PubMed Scopus (130) Google Scholar; Thompson et al. Thompson et al., 2000Thompson DA Gyürüs P Fleischer L Bingham EL McHenry CL Apfelstedt-Sylla E Zrenner E Lorenz B Richards JE Jacobson SG Sieving PA Gal A Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration.Invest Ophthalmol Vis Sci. 2000; 41: 4293-4299PubMed Google Scholar). In the second case (that of patient arRP185), a woman diagnosed with retinitis pigmentosa had an apparently homozygous MERTK mutation, IVS10−2a→g, that was present in heterozygous form in her unaffected father but was not present in her mother (Gal et al. Gal et al., 2000Gal A Li Y Thompson DA Weir J Orth U Jacobson SG Apfelstedt-Sylla E Vollrath D Mutations in MERTK, the human ortholog of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.Nat Genet. 2000; 26: 270-271Crossref PubMed Scopus (507) Google Scholar). Analysis of a number of exonic and intronic, partially informative DNA polymorphisms was consistent with the assumption of a paternal isodisomy, since the patient appeared to be homozygous for one of the paternal alleles (data not shown). Further analysis of 17 informative microsatellite markers spread out along both arms of chromosome 2 suggested complete absence of the maternal homolog (fig. 2). Data obtained for eight other partially informative DNA polymorphisms on chromosome 2 were also consistent with the assumption of paternal isodisomy of chromosome 2. The assumed biological relationship of the patient to her parents was confirmed by analysis of a number of microsatellite markers on chromosomes 3–6, 9, 11, and 14–19 (data not shown). Routine cytogenetic analysis of metaphase chromosome spreads prepared from peripheral blood showed a normal female karyotype (46,XX). Patient arRP185 (currently 34 years of age), the mother of two healthy children, appears phenotypically normal in all aspects except for her retinal disease and a general connective-tissue weakness. She was born after a full-term pregnancy, when her mother and father were 36 and 33 years of age, respectively, and was of normal birth weight. She was noted to be night blind in preschool, and, in primary school, she had poor vision that was uncorrectable by refractive lenses. At 12 years of age, she was diagnosed with retinitis pigmentosa. At 18 years of age, her peripheral vision was largely reduced (10° visual fields). At her current age, she has 5-degree visual fields and has difficulty reading. Her visual handicap is similar to that of the two other retinal dystrophy patients reported to have mutations of MERTK (Gal et al. Gal et al., 2000Gal A Li Y Thompson DA Weir J Orth U Jacobson SG Apfelstedt-Sylla E Vollrath D Mutations in MERTK, the human ortholog of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.Nat Genet. 2000; 26: 270-271Crossref PubMed Scopus (507) Google Scholar). Our studies have identified the first known cases of UPD resulting in retinal degeneration. In both cases, the patient's ocular phenotype appears to result from reduction to homoallelism of a disease-causing mutation of paternal origin, since marker analysis suggests that each patient carries two complete and identical homologs of a single paternal chromosome. Such cases of uniparental isodisomy can be thought of as resulting from compensatory UPD—that is, from replacement of a missing chromosome by early somatic duplication in cases of postzygotic monosomy (Robinson Robinson, 2000Robinson WP Mechanisms leading to uniparental disomy and their clinical consequences.Bioessays. 2000; 22: 452-459Crossref PubMed Scopus (243) Google Scholar). The mutations involved, IVS1+5g→a in RPE65 and IVS10−2a→g in MERTK, are predicted to interfere with correct splicing and to generate loss-of-function alleles of known disease genes that are expressed in the RPE and are necessary for photoreceptor-cell function. The associated ocular phenotypes appear to be very similar to those of other patients who carried mutations in the same genes in homozygous or compound heterozygous form, without additional severe abnormalities in our patients that would indicate multiple autosomal recessive defects, major effects of imprinting, or both. Previous studies have identified UPD involving various chromosomes in patients affected with different autosomal recessive disorders (Engel Engel, 1998Engel E Uniparental disomies in unselected populations.Am J Hum Genet. 1998; 63: 962-966Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Reported cases of UPD of chromosome 1 (UPD 1) involving full or partial isodisomy include a number of cases of maternal UPD 1 (Pulkkinen et al. Pulkkinen et al., 1997Pulkkinen L Bullrich F Czarnecki P Weiss L Uitto J Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa.Am J Hum Genet. 1997; 61: 611-619Abstract Full Text PDF PubMed Scopus (59) Google Scholar; Field et al. Field et al., 1998Field LL Tobias R Robinson WP Paisey R Bain S Maternal uniparental disomy of chromosome 1 with no apparent phenotypic effects.Am J Hum Genet. 1998; 63: 1216-1220Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar; Dufourcq-Lagelouse et al. Dufourcq-Lagelouse et al., 1999Dufourcq-Lagelouse R Lamber N Duval M Viot G Vilmer E Fischer A Prieur M de Saint Basile G Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1.Eur J Hum Genet. 1999; 7: 633-637Crossref PubMed Scopus (45) Google Scholar), as well as cases of paternal UPD 1 (Gelb et al. Gelb et al., 1998Gelb BD Willner JP Dunn TM Kardon NB Verloes A Poncin J Desnick RJ Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis.Am J Hum Genet. 1998; 62: 848-854Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar; Chen et al. 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Takizawa et al., 2000Takizawa Y Pulkkinen L Chao SC Nakajima H Nakano Y Shimizu H Uitto J Complete paternal uniparental isodisomy of chromosome 1: a novel mechanism for Herlitz junctional epidermolysis bullosa.J Invest Dermatol. 2000; 115: 307-311Crossref PubMed Scopus (38) Google Scholar). Of the latter, two are cases of likely complete paternal isodisomy associated with either (a) congenital insensitivity to pain, with anhidrosis due to mutation in TRKA (MIM 191315) (Miura et al. Miura et al., 2000Miura Y Hiura M Torigoe K Numata O Kuwahara A Matsunaga M Hasegawa S Boku N Ino H Mardy S Endo F Matsuda I Indo Y Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis.Hum Genet. 2000; 107: 205-209Crossref PubMed Scopus (34) Google Scholar), or (b) Herlitz junctional epidermolysis bullosa due to mutation in LAMC2 (MIM 150292) (Takizawa et al. Takizawa et al., 2000Takizawa Y Pulkkinen L Chao SC Nakajima H Nakano Y Shimizu H Uitto J Complete paternal uniparental isodisomy of chromosome 1: a novel mechanism for Herlitz junctional epidermolysis bullosa.J Invest Dermatol. 2000; 115: 307-311Crossref PubMed Scopus (38) Google Scholar), with both patients having phenotypes characteristic of autosomal recessive disease but being too young (ages 8 mo and 2 years) to exclude with certainty any additional abnormalities suggestive of an effect of imprinting. Cases of UPD of chromosome 2 (UPD 2) reported elsewhere include a case of paternal i(2p) with maternal i(2q) in a phenotypically normal female with two isochromosomes (Albrecht et al. Albrecht et al., 2001Albrecht B Mergenthaler S Eggermann K Zerres K Passarge E Eggermann T Uniparental isodisomy for paternal 2p and maternal 2q in a phenotypically normal female with two isochromosomes, i(2p) and i(2q).J Med Genet. 2001; 38: 214Crossref PubMed Google Scholar). All other cases were of maternal UPD 2, with four reported cases apparently due to trisomy rescue resulting in uniparental heterodisomy (Harrison et al. Harrison et al., 1995Harrison K Eisenger K Anyane-Yeboa K Brown S Maternal uniparental disomy of chromosme 2 in a baby with trisomy 2 mosaicism in amniotic fluid culture.Am J Med Genet. 1995; 58: 147-151Crossref PubMed Scopus (57) Google Scholar; Webb et al. Webb et al., 1996Webb AL Sturgiss S Warwicker P Robson SC Goodship JA Wolstenholme J Maternal uniparental disomy for chromosome 2 in association with confined placental mosaicism for trisomy 2 and severe intrauterine growth retardation.Prenat Diagn. 1996; 16: 958-962Crossref PubMed Scopus (53) Google Scholar; Hansen et al. Hansen et al., 1997Hansen WF Bernard LE Langlois S Rao KW Chescheir NC Aylsworth AS Smith DI Robinson WP Barrett IJ Kalousek DK Maternal uniparental disomy of chromosome 2 and confined placental mosaicism for trisomy 2 in a fetus with intrauterine growth restriction, hypospadias, and oligohydramnios.Prenat Diagn. 1997; 17: 443-450Crossref PubMed Scopus (52) Google Scholar; Heide Heide et al., 2000Heide E Heide K-G Rodewald A Maternal uniparental disomy for chromosome 2 discovered by exclusion of paternity.Am J Med Genet. 2000; 92: 260-263Crossref PubMed Scopus (21) Google Scholar) and with two reported cases of maternally derived isochromosomes i(2p),i(2q) (Bernasconi et al. Bernasconi et al., 1996Bernasconi F Karagüzel A Celep F Keser I Luleci G Dutly F Schinzel AA Normal phenotype with maternal isodisomy in a female with two isochromosomes: i(2p) and i(2q).Am J Hum Genet. 1996; 59: 1114-1118PubMed Google Scholar; Shaffer et al. Shaffer et al., 1997Shaffer LG McCaskill C Egli CA Baker JC Johnston KM Is there an abnormal phenotype associated with maternal isodisomy for chromosome 2 in the presence of two isochromosomes?.Am J Hum Genet. 1997; 61: 461-462Abstract Full Text PDF PubMed Google Scholar). The case of UPD 2 described in the present study represents the first example of complete paternal isodisomy of chromosome 2, providing evidence, for the first time, that there are no paternally imprinted genes on chromosome 2 that have a major effect on growth or development. The case of UPD 1 described in the present study represents the first example of complete paternal isodisomy of chromosome 1 in an adult individual, establishing that there are no paternally imprinted genes on chromosome 1 that have a major effect on phenotype. In addition, our findings suggest that, in general, the total number of recessive mutations per chromosome in any one individual may be low. It is tempting to speculate that future genetic studies may find that UPD of chromosomes or chromosomal regions unaffected by imprinting may be a more common cause of autosomal recessive disease than has been appreciated previously. We thank the patients for their participation. This study was supported by the Foundation Fighting Blindness, the Deutsche Forschungsgemeinschaft (grant GA 210/12-1), the National Institutes of Health (grants R01-EY05627, R01-EY12298, R01-EY13365, P30-EY07003, and M01-RR00042), the British Retinitis Pigmentosa Society, the German Pro Retina Association, the Macula Vision Research Foundation, the Daniel Matzkin Research Fund, the Ruth and Milton Steinbach Fund, the Karl Kirchgessner Foundation, and Research to Prevent Blindness.