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The Molecular Biology of Norrie's Disease

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The Molecular Biology of Norrie's Disease THE MOLECULAR BIOLOGY OF NORRIE'S DISEASE 2 G. BLACK I and R. M. REDMOND Oxford and London SUMMARY studies on a number of affected pedigrees have mapped The Norrie's disease gene has been accurately located on the gene with increasing accuracy (Fig. 3). Tight linkage the short arm of the X chromosome. The methodology was described to the DNA probe Ll.285 (often referred to underlying this achievement and the structure of the as the X chromosome marker, DXS7). Linkage implies three-exon gene is described in this review article. The that two genetic loci are transmitted together through the clinical implications of these recent advances are dis­ generations of a pedigree more often than would be cussed. Allelic variants of Norrie's disease and the expected by chance - tightly linked loci are physically phenomenon of females affected by X-linked disease are very close on the same chromosome. By observing also discussed. meiotic recombination events between the accurately located DXS7 locus and the unknown NDP locus, it was Norrie's disease (NDP)l was first described in 19272 and, calculated that the two were highly likely to lie within though rare, is well known as an X-linked disorder in approximately I megabase (I Mb, one million nucleotide which affected males have bilateral leucocoria evident in base pairs) of one another. early infancy or even at birth. The leucocoria is due to a Several patients have been described with proximal Xp primary retinal dysplasia and resultant total retinal detach­ deletions which include the DXS7 locus6 or with sub­ ment. Such detachments are of early onset and have been microscopic deletions involving the monoamine oxidase observed by in utero ultrasonograph/ (Fig. I). Secondary genes MAOA & B.7 DNA polymorph isms within MAOA glaucoma, cataract and eventual microphthalmos occur & B� are therefore also closely linked to NDP and their use and are associated, in about one third of cases, with pro­ as DNA markers in informative pedigrees has enabled gressive sensorineural deafness. Mental retardation and more accurate carrier risk estimation and the ability either psychotic behaviour in late childhood is a variable fea­ to diagnose or to exclude Norrie's disease in the male fetus ture.4 Carrier females rarely have any biochemical, ocular of a carrier female. or systemic abnormality. The search for more closely linked DNA markers which In the past few years, huge progress has been made in flank the gene in effect "brackets' the gene locus, and our understanding of the disease through the application allows the application of techniques that examine gen- of modern molecular genetic techniques. This article sur­ veys the progress made in our understanding of NDP and, in so doing, discusses some of the phenomena unique to the X-linked disorders. GENETIC MAPPING OF TH E NDP GENE The NDP gene is located on the short arm of the X chro­ mosome, close to the centromere. The disease locus lies within a region (Xp1 1.4-p11.3) to which other ocular dis­ eases such as XL retinitis pigmentosa (XLRP). congenital stationary night blindness, XL cone dystrophy and XL familial exudative vitreoretinopathy also map (Fig. 2). Since 1985, a series of linkage studies and deletion From: 'Genetics Laboratory. Department of Biochemistry. South Parks Road. Oxford. UK; 'Moorfields Eye Hospital. City Road. London. UK. Fig. 1. In utero ultrasound scan of male fetus at 34 weeks. Correspondence to: Mr R. M. Redmond. Moorfields Eye Hospital. Total retinal detachment is el'ident (By kind permission of Aeo­ City Road. London EC I V 2PD. UK. lus Press.) Eye (1994) 8, 491-496 © 1994 Royal College of Ophthalmologists 492 G. BLACK AND R. M. REDMOND 22.3 Ocular Albinism (OAl) l Xp22.3 X-linked cataract/dental 22.2 Retinoschisis syndrome 22.1 I Xp22.2-22.1 (Nance-Horan syndrome) Xp Xp22.3-21.1 21.3 I Oregon eye disease 21.2 Xp21.3 21.1 X-linked RP, RP3 Cone dystrophy 1 I Xp21.1 X-linked X-linked RP(RP2) 11.4 Norrie disease /FEVR Xp21.1-pl1.3 Congenital stationary 11.3 I Xpl1.4-p11.3 night blindness 11.23 Aland Island eye disease 11.22 Xpll.4-Xpl1.23 11.21 pl1.1/qI1.1 X-linked macular dystrophy 11.2 X peri centromeric 12 13 21.1 Xq 21.2 X-linked megalocornea 21.3 Xq13.3-<j25 Fabry disease 22.1 Xq21.33-<j22 22.2 I Alport's syndrome, Xq22.3 22.3 23 24 Lowe Oculocerebrorenal 25 syndrome Xq25-<j26.1 26 27 X-linked anophthalmos, Xq27-<j28 Colour blindness. 28 I G6PD deficiency Xq28 Hunter disease Fig. 2. Regional mapping of X-linked ophthalmic diseases. 1. Linkage described to anonymous DNA marker DXS7. 7 NDP Disease localised to within 1-5 X 10 bp x .. .. chromosome<:.-__...... __ --. .--__.. (I II I I X<.&.-I--I.-..J.�I.___ •___ •___ ) 2. Small deletions of DXS7, MAOA & B described associated with Norrie disease. Disease localised to within 1-5 X ItP bp I'"NDP 3. Linkage analysis places disease between DXS7 MAOA MAOB MAOB and centromere. 4. The anonymous DNA marker dcU, 150kb from MAOB, defines the centromeric end of a deletion /\ associated with Norrie disease. NDP Disease localised to within 150,000 bp .. .. MAOB del2 Fig. 3. Localisation of the Norrie disease gene. MOLECULAR BIOLOGY OF NORRIE'S DISEASE 493 r---------:--------, Isolate Y AC of 650kb YAC library of 104 separate clones I ----�� containing DXS7, MAOA, I. MAOB and dcl2. 9 Human genomic DNA (l0 bp), digested into fragments of approximately 6 5 X 10 bp, cloned into YAC vector Isolate, by electrophoresis,+ fragment of 160kb between MAOB and dc12. Retinal mRNA, reverse transcribed, Screen cDNA library using 160kb then cloned into bacteriophage. --_�� fragment as radiolabelled DNA probe. \ Retinal eDNA library\ Isolate different cDNAs which are contained within fragment. Fig. 4. Isolation oj" the Norrie disease gene. EXON 1 EXON 2 EXON 3 Genomic DNA. 201bp 380bp 1257bp TATA NDP gene covers approx. 27kb. Intron 1 Intron 2 approx 16kb approx 9kb Transcription, followed by •I splicing of mRNA. 417 815 Mature mRNA, 1.8kb Open reading frame of 399bp. Fig. S. Structure oj" the Norrie disease gene. omic nucleotide sequences between the markers to iden­ mosomal region. In the case of Norrie's disease, the map­ tify the characteristics of a functional gene - the ping of deletions, together with data from linkage candidate gene. analysis, led to accurate localisation of the NDP gene within 150 kb (150 000 nucleotide base pairs). 8 The next step required the utilisation of a specialised PHYSICAL MAPPING AND CLON ING OF vector, the Yeast Artificial Chromosome (YAC) and a TH E NDPGE NE screening procedure using complementary DNA (cDNA) There are two complementary approaches to the cloning libraries from human retinaIO (Fig. 4). cDNA libraries are of disease genes; functional cloning and positional clon­ derived from the messenger RNA (mRNA) of a specific 9 ing. The former refers to a procedure in which a protein, tissue; the reverse transcription of the tissue-specific previously isolated and characterised, is implicated in the mRNA is accomplished with enzymes and the unique aetiology of a disease and is used as the starting point for DNA sequences are then spliced into the DNA of a host the isolation of the gene which encodes it. As no protein vector (e.g. bacteriophage) which allows storage and sub­ was previously implicated in the development of Norrie's sequent retrieval of the cloned cDNA when required. disease, the method of functional cloning was not Chen et al.11 isolated a Y AC containing DXS7, MAOA applicable to the search for the gene involved. & B and NDP and obtained from it, by means of restriction Positional cloning, however, is feasible once a Men­ enzymes and specialised electrophoresis, a 160 kb frag­ delian disorder (i.e. one due to a defect in a single gene) ment of DNA believed to contain all or part of the NDP has been mapped genetically using closely linked DNA gene. This was used to isolate several cDNAs from markers and the disease gene localised to a specific chro- libraries derived from fetal and adult retinal mRNA. Of 494 G. BLACK AND R. M. REDMOND Early female embryonic cell, containing reciprocal translocation between autosome (dark) and X chromsome (light). Translocation passes through the Norrie gene. t Random X inactivation. /'" Translocated X inactive, with inactivation of part of autosome. Part Only these cells survive later in embryogenesis. of translocated X remains active. Cells Intact copy of Norrie gene is inactivated. Female manifests Norrie disease. are functionally disomic for part of the X chromosome and die. Fig. 6. Manifestation of X-linked disease in females with X:autosome translocation. particular interest was one clone which was shown to family of extracellular proteins), the Drosophila slit pro­ hybridise to digests from a wide variety of organisms, tein (an extracellular protein involved in glial develop­ including species as distant as the fruit-fly Drosophila. ment) and von Willebrand coagulation factor. These This suggested that evolution has maintained the DNA proteins show conservation of cysteine residues suggest­ sequence in different species (it is said to be highly con­ ing that they share an identical arrangement of disulphide served) and indicates its probable importance to these bridges. More recent comparative studies indicate that the organisms. The cDNA detected deletions in several NDP protein shares homology and a predicted three­ affected males - including some not previously known to dimensional structure with a carboxy-terminal domain have deletions - and was therefore identified as a can­ (termed the cysteine knot) found as a component in a didate gene for Norrie's disease.
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