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PubMed1995

An efficient screening procedure detecting six novel mutations in the LDL receptor gene in Swedish children with hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal semi-dominant disorder caused by defects in the low density lipoprotein receptor (LDLR) gene and is a well-documented risk factor for developing cardiovascular disease. The LDLR genes of five Swedish children with FH were examined in this study. Initial mutation screening was performed by denaturing gradient gel electrophoresis (DGGE) with enzymatically amplified exon-sized fragments, each containing a tailing GC-rich requence. The GC-clamped fragments had been synthesized with a restriction site adjacent to the intron-corresponding sequence to allow detachment of the clamps, thereby rendering the fragments suitable for subsequent analysis by single-strand conformation polymorphism (SSCP) analysis of samples from patients with no DGGE-detectable mutations. In addition, all the LDLR genes of the patients were screened for large alterations by restriction fragment length polymorphism analysis. Following this strategy, seven different, potentially disease-causing mutations were detected in the five children with FH. Six of the alterations, five single-base substitutions and one dinucleotide deletion, have not previously been described. DGGE detected six of the mutations and SSCP the seventh.

Apolipoproteins↗
PubMed1999

Rapid and efficient ATM mutation detection by fluorescent chemical cleavage of mismatch: identification of four novel mutations.

Mutations in the Ataxia Telangiectasia Mutated (ATM) gene are responsible for the autosomal recessive disease Ataxia Telangiectasia (A-T). A wide variety of mutations scattered across the entire coding region (9168bp) of ATM have been found, which presents a challenge in developing an efficient mutation screening strategy for detecting unknown mutations. Fluorescent chemical cleavage of mismatch (FCCM) is an ideal mutation screening method, offering a non-radioactive alternative to other techniques such as restriction endonuclease fingerprinting (REF). Using FCCM, we have developed an efficient, accurate and sensitive mutation detection method for screening RT-PCR products for ATM mutations. We have identified seven ATM mutations in five A-T families, four of which are previously unknown. We quantified ATM protein expression in four of the families and found variable ATM protein expression (0-6.4%), further evidence for mutant ATM protein expression in both classic and variant A-T patients. We conclude that FCCM offers a robust ATM mutation detection method and can be used to screen for ATM mutations in cancer-prone populations.

Adolescent↗
PubMed2006

Population haplotypes of exon ORF15 of the retinitis pigmentosa GTPase regulator gene in Germany : implications for screening for inherited retinal disorders.

BACKGROUND: Mutations in exon ORF15 of the retinitis pigmentosa GTPase regulator gene (RPGR) within chromosomal region Xp21.1 are a significant cause of a number of retinal disorders. The high mutation rate is ascribed to the highly repetitive, purine-rich tracts within the exon ORF15 sequence. Importantly, all exon ORF15 mutations observed to date represent protein-truncating mutations (nonsense and frameshift mutations). Because of its repetitive motifs, mutation screening of the hot-spot region by direct DNA sequencing is a technically challenging task. METHODS: We devised a screening strategy for exon ORF15 mutations that reserves DNA sequencing for precise sizing and base-order assessment of detected mutations. The screening strategy is based on a PCR/restriction fragment length polymorphism (RFLP) analysis of exon ORF15 and comparison with population-specific RFLP haplotypes. The latter were constructed from PCR/RFLP analysis of DNA samples from 100 healthy German male individuals. Mutational alterations of normal RFLP haplotype patterns were predicted. RESULTS: Six distinct RFLP haplotypes (founder alleles H1-H6) were observed with frequencies ranging from 2% to 63%. All natural variations of exon ORF15 were in-frame alterations ranging in size between 3bp and 36bp. Prediction of mutation-specific RFLP patterns indicated a high detection rate of mutations. CONCLUSION: A new strategy has been developed using routine protocols for mutation screening of difficult-to-sequence, highly repetitive exon ORF15 of the RPGR gene in a German population.

Base Sequence↗
PubMed1994

Reverse dot blot probes for the screening of beta-thalassemia mutations in Asians and American blacks.

We have optimized a battery of reverse dot blot oligonucleotide probes for detecting the most common beta-globin gene mutations in Asians and American Blacks. These probes allow a high degree of coverage of mutant chromosomes in these two populations and are useful in mutation screening and prenatal diagnosis. When coupled with the Mediterranean subset of probes, a 95% worldwide coverage of beta-thalassemia mutations should be possible. The use of these probes in the reverse dot blot system should allow the distribution of premade strips and application to automated screening.

Asian People↗
PubMed2002

First genomic localization of oculo-oto-dental syndrome with linkage to chromosome 20q13.1.

PURPOSE: To characterize the phenotype of autosomal dominant oculo-oto-dental (OOD) syndrome, map the disease locus in a five-generation British family, and evaluate a candidate gene. METHODS: Full clinical assessments in all affected patients included slit lamp and retina examination, refraction, A-scan ultrasound, audiograms, and dental assessments. Genomic DNA from all family members was genotyped, by polymerase chain reaction, for polymorphic genetic markers covering the entire genome. Two-point LOD scores were generated using a linkage analysis suite of computer programs. The gene for eyes absent 2 (EYA2) was screened for mutations by direct automated sequencing and Southern blot analysis. RESULTS: All the affected individuals examined had iris and retina coloboma associated with high-frequency, progressive, sensorineural deafness and globodontia. This is the only genetic disease known to result in pathologically enlarged teeth. The locus for OOD (OOD1) was mapped to 20q13.1. A maximum two-point LOD score of 3.31 was obtained with marker locus D20S836 at a recombination fraction of theta; = 0.00. Two critical recombinations in the pedigree positioned this locus to a region flanked by marker loci D20S108 and D20S159, giving a critical disease interval of 12 centimorgans (cM). Mutation screening of one candidate gene, EYA2, revealed no disease-associated mutations or polymorphic variants. CONCLUSIONS: This is the first genetic localization for the OOD phenotype (ODD1). The disease-causing gene is localized within a 12-cM critical region of chromosome 20q13.1. The identification of the disease gene is not only relevant to the study of vision and hearing defects, but also highlights an exceptional gene involved in the development of human dentition.

Adult↗
PubMed2001

An improved high throughput heteroduplex mutation detection system for screening BRCA2 mutations-fluorescent mutation detection (F-MD).

We describe an improved, fast, automated method for screening large genes such as BRCA2 for germline genomic mutations. The method is based on heteroduplex analysis, and has been adapted for a high throughput application by combining the fluorescent technology of automated sequencers and robotic sample handling. This novel approach allows the entire BRCA2 gene to be screened with appropriate overlaps in four lanes of an ABI 377 gel. The method will detect all types of mutations, especially point mutations, more reliably and robustly than other commonly used conformational sensitive methods (e.g. CSGE). In addition we show that this approach, which relies on band shift detection, is able to detect single base substitutions that have hitherto only been detectable by direct sequencing methods.

BRCA2 Protein↗
PubMedDate not supplied

[Screening of mutations in genes of pro-opiomelanocortin in patients with constitutional exogenous obesity].

Proopiomelanocortin (POMC) is a precursor of ACTH, beta- and gamma-liportopins, alpha-, beta- and gamma-MSH, beta-endorphin. alpha-, beta- and gamma-MSH are synthesized by hypothalamus neurons, and leptin stimulates their synthesis. These hormones regulate food consumption and energy metabolism by via melanocortin receptors (MC3-R and MC4-R) in hypothalamus. Screening mutations in the coding region of human POMC has been carried out with PCR, SSCP and DNA sequencing and the association study of these mutations and human obesity has been performed. Group of patients with the exogenous obesity (BMI 37.8 +/- 6.8 kg/m2) consisted of 228 persons (173 women and 55 men). 145 blood donors (67 women and 78 men) without obesity (BMI J25 kg/m2, 23.1 +/- 2.2 kg/m2) and 170 women without apparent obesity at the beginning of the study were included in the control group. 8 polymorph sites: insertions; missense and silent mutations have been identified in the coding region of POMC. Among them 1) two heterozygous mutations: the insertion of 6 b.p. (GGGCCC) in codon 176 inducing the insertion of two amino acid residues (Arg-Ala) in POMC and nonsense mutation (G-7316-T) in codon 180 of gamma-LTH coding region of the same DNA chain were identified in 4 women (5.8%) out of 69 patients with morbid obesity (BMI 40-53 kg/m2). These mutations were not found in control (n = 315). 2) The new heterozygous mutation T-7130-C (Phe118Leu) in active site of alpha-MSH has been identified in POMC gene of a woman suffering with obesity since the early childhood. 3) Mutation A-7341-G (Glu188Gly) seemed to have a protective effect because it was revealed more frequently in control (3.9%) than in obese patients (0.66%). The results of genetic study of two pedigrees suggested the dominant influence of the first two mutations (1 and 2) on woman obesity.

Adolescent↗
PubMed2004

Absence of mutations in the PCI gene in subfertile men.

The molecular aetiology of male subfertility is still unknown in the majority of cases and it is thought that multiple genes are involved. One of the genes that might play a role in male reproductive function is the protein C inhibitor (PCI) gene. In mice the presence of PCI is an absolute requirement for reproduction. In this study we performed a mutation screen of the PCI gene in subfertile men with severe teratozoospermia or idiopathic azoospermia. Male partners of subfertile couples with idiopathic azoospermia (n = 27) or teratozoospermia (n = 34) and men with normozoospermia (n = 34) were screened for mutations in the PCI gene by direct sequencing. Nine nucleotide variants found in the patients were not present in the initial control group and were therefore screened in an additional control group of 80 men with normozoospermia by restriction fragment length polymorphism analysis. In addition, PCI antigen levels were measured in the seminal plasma of the patients in which a potential mutation was found. In total, three new variants were exclusively present in men with idiopathic azoospermia, but are not likely to have caused the patients' phenotypes. In addition, the PCI antigen levels in seminal plasma of these three patients were not decreased. The fact that we were not able to detect causal mutations in the PCI gene does not necessarily lead to the conclusion that the PCI protein is not involved in human male fertility, but the results of our study indicate that mutations in the human PCI gene are not a common cause of reduced semen parameters in men.

Adult↗
PubMed2006

Hearing genes and cisplatin deafness: a pilot study.

OBJECTIVE: Cisplatin commonly is used to treat pediatric solid tumors. A major dose-limiting toxicity is sensorineural hearing loss. Which patients experience ototoxicity after treatment with cisplatin must reflect individual susceptibility, since it is not seen in all similarly treated patients. We hypothesized that mutations or polymorphisms in hearing genes are more common in patients who experience ototoxicity than in the general population. STUDY DESIGN: We completed retrospective mutation screening of GJB2 and SLC26A4 and screened for three mtDNA mutations in patients with a history of childhood cancer who developed severe hearing loss at cumulative cisplatin doses of less than 400 mg/M2. MATERIALS AND METHODS: Patients younger than 21 years of age who experienced severe hearing loss after cisplatin were identified using the Childhood Cancer Survivor Study database. Archival DNA from buccal washes of 11 patients was used for mutation screening and detection. RESULTS: With the exception of one patient (9.1%) who was a carrier for the 35delG mutation, no mutant alleles were found. Given the reported prevalence of the 35delG mutation in the general population of 2.5%, this result is not significant (P = .35). CONCLUSIONS: It is not likely that any of the five hearing genes we examined contribute to cisplatin ototoxicity. Further study may be warranted to look at other hearing genes as possible predictors of cisplatin ototoxicity.

Adolescent↗
PubMed2004

Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation.

BACKGROUND: A distinct clinical syndrome characterized by megalencephaly, mild to moderate cognitive decline, slowly progressive spasticity, ataxia, occasional seizures, and extensive white matter changes with temporal cysts by imaging studies has been described in a particular ethnic group (Agarwals) in India. This disorder is very similar to megalencephalic leukoencephalopathy with subcortical cysts (MLC), a newly characterized leukodystrophy whose molecular basis was recently shown to be mutations in a gene (KIAA0027) that has been renamed MLC1. OBJECTIVE: To determine if this disorder among the Agarwals is due to mutations in MLC1 by a mutation screening study conducted on affected Agarwal patients. METHODS: Genomic DNA from these Indian leukodystrophy patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the MLC1 gene. RESULTS: Thirty-three affected individuals whose clinical and imaging presentations were consistent with MLC were screened. All were from northern India and included 31 known Agarwals, 1 non-Agarwal, and 1 adopted patient whose ethnicity is unknown. All 31 Agarwal patients tested positive for a homozygous insertion of a cytosine in exon 2. The adopted patient was homozygous for A157E. No mutation in the coding region was found in the non-Agarwal patient. CONCLUSIONS: Indian patients with megalencephaly and MRI changes that show extensive white matter changes with temporal cysts should raise suspicion for MLC. Members of the Agarwal ethnic group affected with the disorder present with a mildly progressive course and show a common mutation (320insC) in the MLC1 gene, suggesting a founder effect.

Adolescent↗
PubMed2002

Genetic screen yields mutations in genes encoding all known components of the Escherichia coli signal recognition particle pathway.

We describe the further utilization of a genetic screen that identifies mutations defective in the assembly of proteins into the Escherichia coli cytoplasmic membrane. The screen yielded mutations in each of the known genes encoding components of the E. coli signal recognition particle pathway: ffh, ffs, and ftsY, which encode Ffh, 4.5S RNA, and FtsY, respectively. In addition, the screen yielded mutations in secM, which is involved in regulating levels of the SecA component of the bacterium's protein export pathway. We used a sensitive assay involving biotinylation to show that all of the mutations caused defects in the membrane insertions of three topologically distinct membrane proteins, AcrB, MalF, and FtsQ. Among the mutations that resulted in membrane protein insertion defects, only the secM mutations also showed defects in the translocation of proteins into the E. coli periplasm. Genetic evidence suggests that the S382T alteration of Ffh affects the interaction between Ffh and 4.5S RNA.

ATP-Binding Cassette Transporters↗
PubMed2001

Genetic analysis of the INSL3 gene in patients with maldescent of the testis.

OBJECTIVE: Testicular maldescent is important because it is a common congenital disorder that is associated with an increased risk of infertility and testicular cancer. Murine studies indicate that testicular maldescent can result from disruption of insulin-like factor 3 (INSL3) activity and that it may be more severe when there is concurrent undermasculinisation. Therefore, the INSL3 gene was screened for mutations and polymorphisms that may contribute to testicular maldescent in patients with undermasculinisation as well as those with isolated testicular maldescent. METHODS AND RESULTS: The patient groups consisted of individuals with isolated testicular maldescent (n=28) and patients with undermasculinised genitalia and intra-abdominal (n=24) or inguinal gonads (n=33). The three control groups were: normal males (n=15), males with undermasculinised genitalia and scrotal gonads (n=29) and females (n=82). SSCP/HA mutation screening detected eight variants, five of which were predicted to alter the protein sequence (A-1G, V19L, P25S, A36T, R78H). Three of the amino acid changes (A-1G, V19L, R78H) each occurred in a single control sample and one was identified in a male with undermasculinised genitalia and intra-abdominal testes (P25S). The A36T amino acid polymorphism was found in both patient and control groups at a similar frequency. CONCLUSIONS: The evidence suggests that INSL3 mutations and polymorphisms are not a major cause of testicular maldescent with or without associated undermasculinisation.

Amino Acid Sequence↗
PubMed2004

Alkaptonuria, ochronosis, and ochronotic arthropathy.

OBJECTIVES: To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition. METHODS: We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers. RESULTS: Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane. CONCLUSIONS: Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.

Aged↗
PubMed2002

Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines.

The tumor-suppressor genes p14(ARF), p16(INK4a) and Tp53 are commonly inactivated in many tumors. We investigated their role in the pathogenesis of 9 bile tract cancer cell lines and 21 primary sporadic extrahepatic bile duct carcinomas. p53 and p16 protein expression was examined by Western blot analysis and immunohistochemistry. Mutation screening of p53 was done by SSCP and direct sequencing. Inactivating mechanisms of p14 and p16 were addressed by screening for mutations, homozygous deletions, chromosomal loss of 9p21 (loss of heterozygosity [LOH] analysis) and promoter hypermethylation of the p14/p16 genes. p53 overexpression could be detected in 7 of 9 cell lines and 7 of 21 primary tumors, but mutations were found in 3 cell lines only. p16 expression was absent in all cell lines, due to homozygous deletion of the gene in 8 of 9 cell lines and hypermethylation of the p16 promoter in one cell line (CC-LP-1). p14 exon 1beta was homozygously deleted in 6 of 9 cell lines, while retained in CC-LP-1 and 2 additional lines. No p14 promoter hypermethylation could be detected. p16 expression was lost in 11 of 21 primary tumors. p16 promoter hypermethylation was present in 9 of 21 primary tumors, all with lost p16 expression. Allelic loss at 9p21 was detected in 13 of 21 primary tumors, 10 of 11 with lost p16 expression and 8 of 9 with methylated p16 promoter. No p14 promoter hypermethylation or p14/p16 mutations could be detected. Neither Tp53 nor p16 alterations showed obvious association with histopathologic or clinical characteristics. In conclusion, inactivation of the p16 gene is a frequent event in primary sporadic extrahepatic bile duct cancers, 9p21 LOH and promoter hypermethylation being the principal inactivating mechanisms. Therefore, p16, but not p14, seems to be the primary target of inactivation at the INK4a locus in bile duct cancers. Other mechanisms than Tp53 mutations seems to be predominantly responsible for stabilization of nuclear p53 protein in bile duct cancers.

Bile Duct Neoplasms↗
PubMed2007

Balance between endoscopic and genetic information in the choice of ileorectal anastomosis for familial adenomatous polyposis.

BACKGROUND AND OBJECTIVES: The number of rectal polyps and the site of mutations in the APC (Adenomatous polyposis coli) gene have been used to guide the surgical management in patients with familial adenomatous polyposis (FAP). The aim of this study is to assess the utility of the APC mutation screening compared to the degree of the rectal polyposis in surgical decision making. METHODS: The post-surgical courses of 25 patients submitted to subtotal colectomy with ileorectal anastomosis (IRA) were reviewed. Preservation of the rectum was prospectively decided on the basis of well-defined endoscopic criteria. The number of rectal polyps was assessed preoperatively and every 6-12 months. APC gene was screened for mutations by heteroduplex analysis, single strand conformation polymorphism, in vitro synthesized protein (IVSP), and DNA sequencing. Patients negative for APC mutations were tested for MYH mutations. RESULTS: On the basis of preoperative polyp rectal count we categorized patients as follows: Group I, 5 or fewer adenomas; Group II, 6-9 adenomas; Group III, 10 or more adenomas. After a follow-up ranging from 12 to 225 months we have observed a significant difference of recurrent rectal adenomas between Groups I-II versus III. No difference was detected among patients of Group I and II. The mean number of adenomas/year/patient was 0.67, 1.62, and 9.29 for Group I, II, and III, respectively. Carpeting polyposis of the rectal stump developed in three patients with APC mutation at codon 1309 and two of them needed later proctectomy. Diffuse rectal polyposis was observed in one patient with mutation at exon 9 who had 10 small polyps at time of surgery. Mutation at the 5'-end of APC (codons 144-232), mutation of MYH and unknown APC or MYH mutation were correlated with a low number of polyps both at presentation and follow-up. No IRA patients developed rectal cancer. CONCLUSIONS: In our experience fewer than 10 rectal polyps at presentation can predict a favorable outcome after IRA. Identification of specific germ-line APC or MYH mutation can address the choice of surgical treatment.

Adenomatous Polyposis Coli↗
PubMed1994

Polymerase chain reaction heteroduplex polymorphism analysis by entangled solution capillary electrophoresis.

Heteroduplex DNA polymorphism analysis (HPA) makes use of conformational polymorphisms to alter electrophoretic mobility of fragments and can be used to detect non-restrictable loci. We have developed a novel application of entangled solution capillary electrophoresis (ESCE) to separate heteroduplex and homoduplex DNA molecules. The addition of ethidium bromide and glycerol to the free solution sieving buffer resulted in the improved peak resolution and good reproducibility. Reannealed polymerase chain reaction products could be used directly for mutation screening and with fully automated ESCE the entire HPA may be completed in less than 30 min including sample handling. This technology could provide a rapid and highly efficient way for screening rare mutations among large numbers of individuals.

Base Sequence↗
PubMed2005

Clinical, electrophysiological and molecular genetic studies in a family with X-linked dominant Charcot-Marie-Tooth neuropathy presenting a novel mutation in GJB1 Promoter and a rare polymorphism in LITAF/SIMPLE.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of neuropathies. In the demyelinating form of Charcot-Marie-Tooth disease with dominant inheritance, five genes have been incriminated: PMP22, MPZ, LITAF/SIMPLE, EGR2 (CMT1A to D), and GJB1 (CMTX). Here, we report clinical, electrophysiological and molecular genetic studies in a family with a Charcot-Marie-Tooth disease variable phenotype, ranging from asymptomatic to moderately affected. The absence of male-to-male transmission as well as the results of systematic electrophysiological studies suggested a CMTX secondary to a GJB1 mutation. Screening for mutations in the coding regions of PMP22, MPZ, EGR2 and GJB1 was negative. We identified (1) a LITAF/SIMPLE substitution (T49M), absent in 1000 control chromosomes, but which was thought to be a polymorphism because of discrepancies of segregation when considering the results of electrophysiology; and (2) a novel substitution T>C in the P2 promoter of GJB1 at position -529, in the SOX10 binding site S2. The transmission of this second mutation was consistent with the electrophysiological data. We emphasise the role of electrophysiological studies that help to discriminate between asymptomatic subjects and that bring some additional valuable data to the genetic approach.

Adolescent↗
PubMed2005

Mutation in the gene GUCA1A, encoding guanylate cyclase-activating protein 1, causes cone, cone-rod, and macular dystrophy.

PURPOSE: To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 4-generation family and to examine the phenotype and the degree of intrafamilial variability. DESIGN: Prospective case series. PARTICIPANTS: Six affected individuals from a nonconsanguineous British family. METHODS: Detailed ophthalmologic examination, color fundus photography, autofluorescence imaging, and electrophysiologic assessment were performed. Blood samples were taken for DNA extraction, and mutation screening of GUCA1A, the gene encoding guanylate cyclase-activating protein 1 (GCAP1), was undertaken. RESULTS: All affected subjects complained of mild photophobia and reduced central and color vision. Onset was between the third and fifth decade, with subsequent gradual deterioration of visual acuity and color vision. Visual acuity ranged between 6/9 and counting fingers. Color vision was either absent or markedly reduced along all 3 color axes. A range of macular appearances was seen, varying from mild retinal pigment epithelial disturbance to extensive atrophy. Electrophysiologic testing revealed a range of electrophysiologic abnormalities: isolated cone electroretinography abnormalities, reduced cone and rod responses (with cone loss greater than rod), and isolated macular dysfunction. The 4 coding exons of GUCA1A were screened for mutations in affected and unaffected family members. A single transition, A319G, causing a nonconservative missense substitution, Tyr99Cys, segregated uniquely in all affected subjects. CONCLUSIONS: The Tyr99Cys GUCA1A mutation has been previously shown to cause autosomal dominant progressive cone dystrophy. This is the first report of this mutation also causing both cone-rod dystrophy and isolated macular dysfunction. The phenotypic variation described here exemplifies the intrafamilial heterogeneity of retinal dysfunction that can be observed in persons harboring the same mutation and chromosomal segment.

Adult↗