眼白化病1型的分子病理生理基础

Ocular albinism type 1 (OA1), the most form of the ocular albinism, is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina, photophobia, strabismus and nystagmus. The OA1 gene is located on chromosome Xp22.32 and the coding sequence is divided into nine exons. The OA1 gene codes for a 404 amino acid protein thought to be a melanosomal transmembrane glycoprotein. The OA1 protein is similar to the G protein-coupled receptors, but it‘s exact function is not clear. There are many mutations and deletions of the OA1 gene have been found.     

Analysis of a terminal Xp22.3 deletion in a patient with six monogenic disorders: implications for the mapping of X linked ocular albinism.

The molecular characterisation of chromosomal aberrations in Xp22.3 has established the map position of several genes with mutations resulting in diverse phenotypes such as short stature (SS), chondrodysplasia punctata (CDPX), mental retardation (MRX), ichthyosis (XLI), and Kallmann syndrome (KAL). We describe the clinical symptoms of a patient with a complex syndrome compatible with all these conditions plus ocular albinism (OA1). He has a terminal Xp deletion of at least 10 Mb of DNA. Both the mother and sister of the patient are carriers of the deletion and show a number of traits seen in Turner's syndrome. The diagnosis of ocular albinism was confirmed in the patient and his mother, who shows iris translucency, patches and streaks of hypopigmentation in the fundus, and macromelanosomes in epidermal melanocytes. By comparative deletion mapping we can define a deletion interval, which locates the OA1 gene proximal to DXS143 and distal to DXS85, with the breakpoints providing valuable starting points for cloning strategies.     

Carrier detection in X-linked ocular albinism of the Nettleship-Falls type by DNA analysis

X-linked ocular albinism (XOA) is characterized by anomalies of the eyes and hypopigmentation or absence of pigment in skin, hair and eyes due to a hereditary inborn error of metabolism affecting the pigment cells. The gene of XOA of the Nettleship-Falls type (OA1) has been mapped to Xp22.3, and several closely linked RFLP loci have been identified. Linkage analysis and deletion mapping have established the marker gene order Xpter-STS-DX237-(OA1,DXS143,DXS85)-DXS1 6-DXS43-Xcen. Although the position of OA1 has yet not been fully resolved, we report on the first carrier detections in OXA of the Nettleship-Falls type by DNA analysis using markers which unquestionably flank OA1.     

Normal intelligence and social interactions in a male patient despite the deletion of NLGN4X and the VCX genes

Xp22.3 deletion in males can be associated with short stature (SHOX), chondrodysplasia punctata (ARSE), mental retardation (MRX49 locus), ichthyosis (STS), Kallmann syndrome (KAL1) and ocular albinism (OA1), according to the size of the deletion. Studies of terminal and interstitial deletions in male patients with a partial nullisomy of the X chromosome have led to the identification of the VCX-3A gene at the MRX49 locus on Xp22.3. The NLGN4X gene has then been identified less than 350 kb away from VCX-3A. Nonsense mutations in NLGN4X have been associated with autism and/or moderate mental retardation in males. We report a 17-year old male patient presenting with severe ichthyosis and Kallmann syndrome related to a 3.7 Mb interstitial Xp22.3 deletion, encompassing STS and KAL1 genes, respectively. However, despite the deletion of NLGN4X and all VCX genes, including VCX-3A, our patient did not manifest any learning disabilities or behavioural problems. Therefore, our case argues against a major role of NLGN4X and the VCX genes alone in cognitive development and/or communication processes.     

Genomic screen for loci associated with tobacco usage in Mission Indians

Background

Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene.

Methods

The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments.

Results

We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found.

Conclusion

The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand.     

New insights into ocular albinism type 1 (OA1): Mutations and polymorphisms of the OA1 gene

Albinism ocular type 1 (OA1) is an X‐linked type of albinism that mainly effects pigment production in the eye, resulting in hypopigmentation of the retina, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers, and reduced visual acuity. The OA1 gene is located on chromosome Xp22.32 and the coding sequence is divided into nine exons. The protein is an integral transmembrane protein that has weak similarities to G protein‐coupled receptors. A total of 25 missense, two nonsense, nine frameshift, and five splicing mutations have been reported in the OA1 gene associated with OA1. There are also several deletions of some or all exons of the OA1 gene with deletions of exon 2 resulting from unequal crossing‐over, due to flanking Alu repeats. Mutation and polymorphism data on this gene is available from the International Albinism Center – Albinism Database web site ( http://www.cbc.umn.edu/tad ). Hum Mutat 19:85–92, 2002. © 2002 Wiley‐Liss, Inc.     

Genetic mapping of the Kallmann syndrome and X linked ocular albinism gene loci.

The X linked form of Kallmann syndrome (KAL) and X linked ocular albinism (OA1) have both been mapped to Xp22.3. We have used a dinucleotide repeat polymorphism at the Kallmann locus to type 17 X linked ocular albinism families which had previously been typed for the Xg blood group (XG) and the DNA markers DXS237 (GMGX9), DXS143 (dic56), and DXS85 (782). Close linkage was found between KAL and OA1 with a maximum lod score (Zmax) of 30.14 at a recombination fraction (theta max) of 0.06 (confidence interval for theta: 0.03-0.10). KAL was also closely linked to DXS237 (Zmax = 15.32; theta max = 0.05; CI 0.02-0.12) and DXS143 (Zmax = 14.57; theta max = 0.05; CI 0.02-0.13). There was looser linkage to the Xg blood group (XG) and to DXS85 (782). Multipoint linkage analysis gave the map: Xpter-XG-0.13-DXS237-0.025-KAL-0.025-DXS143-0.01 5-OA1-0.09-DXS85-Xcen. Placement of OA1 proximal to DXS143 was supported by odds of 2300:1 compared to other orders. This confirms our previous localisation of OA1 and improves the genetic mapping of both disease loci.     

Ocular albinism with infertility and late‐onset sensorineural hearing loss

Ocular albinism type 1 (OA1) is caused by mutations in the GPR143 gene located at Xp22.2. The manifestations, which are due to hypopigmentation, are confined to the eyes and optic pathway. OA1 associated with late‐onset sensorineural hearing loss was previously reported in a single family and hypothesized to be caused by a contiguous gene deletion syndrome involving GPR143 and the adjacent gene, TBL1X. Here, we report on a family with OA1, infertility, late‐onset sensorineural hearing loss, and a small interstitial Xp microdeletion including the GPR143, TBL1X, and SHROOM2 genes. In addition, we re‐examined a patient previously described with OA1, infertility and a similar Xp deletion with audiologic follow‐up showing a late‐onset sensorineural hearing loss. Our results raise an intriguing question about the possibility for TBL1X (absence) involvement in this type of hearing loss. However, our study cannot claim a causative relationship and more convincing evidence is needed before the hypothesis can be accepted that TBL1X could be involved in late‐onset sensorineural hearing loss and that ocular albinism with late‐onset sensorineural hearing loss can present itself as a contiguous gene deletion/microdeletion syndrome. The finding of infertility in all affected male patients demonstrates that this deletion, including the SHROOM2 gene, may be a potentially causative X‐linked genetic factor of male infertility.     

Genetic mapping of X linked ocular albinism: linkage analysis in British families.

Genetic linkage studies were performed in 16 British families affected by X linked ocular albinism (XLOA) using RFLPs from the Xp22.3 region. Linkage was confirmed between the XLOA locus (OA1) and the loci DXS143 (dic56; Zmax = 15.90 at theta = 0.0, confidence interval (CI) 0-0.035), DXS85 (782; Zmax = 15.67 at theta = 0.04, CI = 0.007-0.11), and DXS237 (GMGX9; Zmax = 12.65 at theta = 0.08, CI = 0.03-0.17). Multipoint linkage analysis placed OA1 between DXS85 (782) and DXS237 (GMGX9) with odds exceeding 10(4):1 to give the map DXS85-(OA1,DXS143)-DXS237-XG-Xpter. OA1 lies close to DXS143 (dic56) but in the absence of recombinants the order of these loci could not be determined.     

A male infant with a 9.6 Mb terminal Xp deletion including the OA1 locus: Limit of viability of Xp deletions in males

Males with deletions of or within Xp22.3-pter display variable contiguous gene syndromes including manifestations of Léri-Weill syndrome, chondrodysplasia punctata, mental retardation, ichthyosis, Kallmann syndrome, and ocular albinism. Herein, we report on a male infant with a large, cytogenetically visible, terminal Xp deletion defined by extensive FISH and STS marker analysis to encompass 9.6 Mb, and findings of all of the disorders mentioned above. His deletion approximates the largest Xp terminal deletion ever reported in a male individual. Since the extent of terminal Xp deletions viable in males is limited by the position of male lethal genes in Xp22.2 at about 10-11 Mb from the telomere, this patient falls into the category of the most severe male terminal Xp deletion phenotype.     

Two hot spots of recombination in the DMD gene correlate with the deletion prone regions.

Genetic mapping has indicated that meiotic recombination occurs about 4 time more frequently in the dystrophin gene than expected on the basis of its length. To detect where recombinations occur within the gene, we have studied the CEPH families panel using highly polymorphic microsatellite markers located at the ends of the gene or flanking the major deletion hot spot in intron 44. We found a major hot spot of recombination between markers STR44 and STR50(1), i.e., between exons 44 and 51. Within this hot spot, a peak of recombination was located in the large intron 44. A second minor recombination prone region was found between DXS 206, (XJ, in the large intron 7) and the 5' end of the DMD gene. The distribution of the recombination events in the gene of healthy individuals was very similar to that of deletion breakpoints in DMD/BMD patients, suggesting that the two phenomenon may share a common mechanism. These results should also improve efficiency and accuracy of linkage analysis applied to carrier detection and prenatal diagnosis. In particular, if markers located at the very 3' end of the gene are not informative, the highly polymorphic ones located between exons 50 and 60 can be used instead of presently available extragenic markers, with a very low risk of diagnostic error due to recombination.     

Characterisation of a 161 kb deletion extending from the NBR1 to the BRCA1 genes in a French breast-ovarian cancer family

A large germline deletion removing exons 1 to 22 of the BRCA1 gene has been previously detected using quantitative PCR based methods (QMPSF and real time PCR gene dosage assay) in a woman affected with breast and ovarian cancer. Here, we report its characterisation by using colour bar code on combed DNA of the BRCA1 region. The 5' boundary is located in a Alu Y sequence in NBR1 intron 18 whereas the 3' boundary is located in a Alu Sc sequence in BRCA1 intron 22. This 161 kb deletion encompassing the NBR1, PsiBRCA1, NBR2 and BRCA1 genes is the largest BRCA1 deletion reported so far. No specific phenotype was associated with the hemizygosity of these four genes.     

Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations

Inherited mutations of a purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8), give rise to Lesch-Nyhan syndrome or HPRT-related gout. We have identified a number of HPRT mutations in Asian patients manifesting different clinical phenotypes, by analyzing all nine exons of the HPRT gene (HPRT1) from genomic DNA and reverse-transcribed mRNA using the PCR technique coupled with direct sequencing. In this study, we update the spectrum of mutations with nine novel mutations. Two missense mutations (T124P and D185G) were detected in patients with HRH (HPRT-related hyperuricemia). In a patient having a severe partial deficiency of HPRT with neurological dysfunction (HRND: HPRT-related neurological dysfunction), a single nucleotide substitution (27+5G > A) causing a splicing error was found in intron 1. The mutation resulted in a remarkably decreased level of normal mRNA, and production of an abnormal mRNA with a 49-bp insert at the 5'-end of intron 1, which caused the frame-shift of an amino acid codon (10fs27X). In six typical Lesch-Nyhan families, we found two 3-bp deletions responsible for single amino acid deletions (V8del and Y28del), two 1-bp deletions (440delA and 635delG) generating a frame-shift, an insertion of two amino acids (159insKV), and a 4,131-bp deletion from introns 4 to 6 resulting in two types of abnormal mRNA. Including these nine mutations, 42 HPRT1 mutations have been identified among 47 Asian families with deficiency of HPRT.     

Mental retardation in a boy with an interstitial deletion at Xp22.3 involving STS,KAL1, and OA1: Implication for the MRX locus

Although genotype-phenotype correlations in male patients with various types of nullisomy for Xp22.3 have assigned a locus for X-linked mental retardation (MRX) to an approximately 3-Mb region between DXS31 and STS, the precise location has not been determined. In this paper, we describe a 14 7/12 year old Japanese boy with mental retardation and an interstitial deletion at Xp22.3 involving STS, KAL1, and OA1, and compare the deletion map with that of previously reported three familial male patients with low-normal intelligence and a similar interstitial deletion at Xp22.3. The results suggest that the MRX gene is further localized to the roughly 1.5-Mb region between DXS1060 and DXS1139. © 1996 Wiley-Liss, Inc.     

Genomic structure of a human holocytochrome c-type synthetase gene in Xp22.3 and mutation analysis in patients with Rett syndrome

The human holocytochrome c-type synthetase (HCCS) gene is located on Xp22.3 and is one of the genes identified in a 450-Kb region deleted in the neurodevelopmental disorder microphthalmia with linear skin defects. Several other developmental disorders with or without a neurological phenotype have been linked to Xp22.3. This region of the X chromosome was also found to be concordant in patients with Rett syndrome (RTT)in previously performed exclusion mapping. Based on its chromosomal location and its role in the mitochondrial respiratory chain, we analyzed HCCS as a candidate gene for RTT. The genomic structure of this gene, which occupies an 11-Kb region and consists of seven exons, was determined. All intron-exon boundaries were sequenced and primers were designed for polymerase chain reaction (PCR) amplification of each coding exon. PCR-amplified products from genomic DNA isolated from 20 RTT patients were screened for mutations using heteroduplex analysis. No mutations were detected. The genomic characterization of this gene will allow us to perform mutation analysis for other inherited disorders linked to this region. Am. J. Med. Genet. 78:179–181, 1998. © 1998 Wiley-Liss, Inc.     

The gene for incontinentia pigmenti: failure of linkage studies using DNA probes to confirm cytogenetic localization

Probes for restriction fragment length polymorphisms mapping between Xp21 and Xq22.3 have been used in a linkage study of incontinentia pigmenti (IP). Six independent sporadic cases of disorders resembling IP with X-autosome translocations involving the same X chromosome breakpoint (Xp11) have been reported. These observations suggest that the IP gene may be located in the Xp11 chromosomal region. However, the linkage study with DNA probes has failed to confirm this localisation.     

No mutations detected in the INSR gene in a chromosome 19p13 linked migraine pedigree

The aim of this study was to investigate through direct sequencing the insulin receptor (INSR) gene in DNA samples from a migraine affected family previously showing linkage to chromosome 19p13 in an attempt to detect disease associated mutations. Migraine is a common debilitating disorder with a significant genetic component. At present, the number and type of genes involved in the common forms of migraine are not clear. The INSR gene on chromosome 19p13.3-13.2 is a gene of interest since a number of single nucleotide polymorphisms (SNPs) located within the gene have been implicated in migraine with (MA) and without aura (MO). Six DNA samples obtained from non-founding migraine affected members of migraine family 1 (MF1) were used in this study. Genomic DNA was sequenced for the INSR gene in exons 1-22 and the promoter region. In the six migraine family member samples, previously reported SNPs were detected within two exonic DNA coding regions of the INSR gene. These SNPs, in exons 13 and 17, do not alter the normal INSR polypeptide sequence. In addition, intron 7 also revealed a DNA base sequence variation. For the 5' untranslated promoter region of the gene, no mutations or polymorphisms were detected. In conclusion, this study detected no INSR mutations in affected members of a chromosome 19 linked migraine pedigree. Hence, migraine linkage to this chromosomal region may involve other candidate genes.