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PubMed2006

Posttransplant recurrence of proteinuria in a case of focal segmental glomerulosclerosis associated with WT1 mutation.

Posttransplant recurrence of inherited focal segmental glomerulosclerosis (FSGS) is still an enigma owing to the evident paradox of the molecular origin of proteinuria. A young girl with FSGS for WT1 mutation (IVS9+4C>T) and Frasier syndrome received a renal transplant at the age of 11 years. After an initial good outcome with recovery of renal function, proteinuria re-appeared after 7 days and steadily increased up to a nephrotic range. Determination of plasma permeability activity showed concomitant high Palb (0.7). At this point, plasmapheresis was started and after nine cycles with 1500 mL exchange and albumin re-infusion, proteinuria decreased to normal range and is still normal after 3 years. This is the first description of posttransplant recurrence of proteinuria in Frasier syndrome that should be included in potential outcome of renal transplant in this category of patients. This observation confirms the concept that recurrence of proteinuria may occur in inherited forms of FSGS so far reported only for patients carrying NPHS2 mutations and reinforces the idea on multifactorial origin of the disease.

Adolescent↗
PubMed2004

Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism.

Mutations in the gene coding for hepatocyte nuclear factor-1beta (HNF-1beta) have been known to cause a form of maturity-onset diabetes of the young (MODY5), which is usually characterized by dominantly inherited adolescence-onset diabetes mellitus associated with renal cysts. This report, however, describes recurrence of a novel missense mutation in the HNF-1beta gene, S148W (C443G), in two sibs, one with neonatal diabetes mellitus and the other with neonatal polycystic, dysplastic kidneys leading to early renal failure. The former patient had only a few small renal cysts with normal renal functions, and the latter had only a transient episode of hyperglycemia, which resolved spontaneously. Interestingly, both parents were clinically unaffected, and PCR restriction fragment length polymorphism analysis showed that the mother was a low-level mosaic of normal and mutant HNF-1beta, which suggested that the recurrence was caused by germline mosaicism. This is the first report of permanent neonatal diabetes mellitus caused by a mutation of the HNF-1beta gene as well as the first report of germline mosaicism of this gene. In addition, the two cases described here show that additional factors, genetic or environmental, can have a significant influence on the phenotypic expression of HNF-1beta mutations.

Child↗
PubMed1995

Recurrent simple tandem repeat mutations during human Y-chromosome radiation in Caucasian subpopulations.

The haplotypes at four polymorphic loci of the Y chromosome were determined in 245 Caucasian males from 12 subpopulations. The data show that haplotype radiation occurred among Caucasians. Haplotype radiation was accompanied by recurrent mutations at STR loci that caused partial randomization of haplotype structure. The present distribution of alleles at short tandem repeats (STRs) can be explained by a mutation pattern similar to those described for autosomal STRs. The degree of variation among groups of subpopulations was assayed by using the Analysis of Molecular Variance. The results confirm a faster divergence of the Y chromosome as compared to the rest of the genome.

Haplotypes↗
PubMed2005

Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome.

Marfan syndrome (MFS) is an autosomal-dominant disorder of the fibrous connective tissue that is typically caused by mutations in the gene coding for fibrillin-1 (FBN1), a major component of extracellular microfibrils. The clinical spectrum of MFS is highly variable and includes involvement of the cardiovascular, skeletal, ocular, and other organ systems; however, the genotype-phenotype correlations have not been well developed. Various screening methods have led to the identification of about 600 different mutations (FBN1-UMD database; www.umd.be). In this study we performed SSCP and/or direct sequencing to analyze all 65 exons of the FBN1 gene in 116 patients presenting with classic MFS or related phenotypes. Twenty-nine novel and nine recurrent mutations were identified in 38 of the analyzed patients. The mutations comprised 18 missense (47%), eight nonsense (21%), and five splice site (13%) mutations. Seven further mutations (18%) resulted from deletion, insertion, or duplication events, six of which led to a frameshift and subsequent premature termination. Additionally, we describe new polymorphisms and sequence variants. On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutation-positive patients for whom comprehensive clinical data were available. Most strikingly, there was a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon (PTC) or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration.

Amino Acid Sequence↗
PubMed2004

Distribution, type, and origin of Parkin mutations: review and case studies.

Early-onset Parkinson's disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty-eight mutation-positive individuals, available family members, and 62 mutation-negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type.

Adult↗
PubMed2002

Prothrombin G20210A mutation is not associated with recurrent miscarriages.

OBJECTIVE: To assess the association between prothrombin G20210A mutation and recurrent miscarriages. STUDY DESIGN: A literature review was performed in Medline identifying articles from 1966 to December 2000. Articles meeting inclusion criteria were systematically reviewed and included in a meta-analysis. RESULTS: Six trials, all case-controlled, were identified. These trials included 323 women with recurrent pregnancy loss. The odds ratio (OR) for heterozygous prothrombin mutation was 1.9 (95% confidence interval (CI) 0.98-4.14), and for homozygous prothrombin mutation was 3.76 (95% CI 0.75-18.77). The OR for prothrombin mutation and primary recurrent abortion was 2.19 (95% CI 0.61-7.89) and for prothrombin mutation and secondary recurrent abortion was 1.29 (95% CI 0.2-8.36). CONCLUSION: There is no evidence to support an association of prothrombin G20210A mutation with recurrent miscarriages.

Abortion, Habitual↗
PubMed2003

Breast cancer genetics in African Americans.

BACKGROUND: An overview of the state of genetic testing for BRCA1 and BRCA2 genes was presented at the Summit Meeting on Breast Cancer Among African American women. METHODS: An exhaustive literature search was performed using PubMed and abstracts published from meetings of the American Association for Cancer Research, the American Society of Human Genetics, and the American Society of Clinical Oncology. The Breast Cancer Information Core was also searched for information regarding sequence variants in which the ethnicity of the individual tested was known. RESULTS: Of the 26 distinct BRCA1 pathogenic mutations (protein-truncating, disease-associated missense, and splice variants) detected in Africans or African Americans, 15 (58%) have not been previously reported. In addition, 18 deleterious BRCA2 mutations have been identified and 10 (56%) of these are unique to the group. Only two pathogenic BRCA1 mutations (943ins10 and M1775R) have been detected in three or more unrelated families. However, seven additional BRCA1 or BRCA2 deleterious mutations have been reported in at least two unrelated families. Three of these recurrent BRCA1 mutations (943ins10, 1832del5, and 5296del4) have been characterized by haplotype studies and each likely arose from a common ancestor, including one ancestor that could be traced to the Ivory Coast in West Africa. Although only a few African-American families have been tested for BRCA1 and BRCA2 mutations, the probability of finding a mutation is invariably dependent on the age of onset and the number of breast and/or ovarian cancer cases in the family. The psychosocial implications of genetic testing for African Americans have not been well studied, so that high-risk African Americans may underestimate their risks of breast and ovarian cancer. CONCLUSIONS: Deleterious BRCA1 and BRCA2 mutations have been identified in African-American and African families. A number of unique mutations have been described, but recurrent mutations are widely dispersed and are not readily identifiable in the few families that have been tested. Access to genetic counseling and testing in a culturally sensitive research setting must remain a high priority before genetic testing can be disseminated in the community.

Black People↗
PubMed1998

[Molecular diagnosis of mutations responsible for recurrent and severe forms of primary congenital glaucoma].

A PCR-based test has been developed that makes it possible to detect a G to A substitution in the cytochrome P4501B1 gene. This mutation brings about a substitution of glutamic acid to lysine in the cytochrome P4501B1 molecule, and has been shown to be responsible, in homozygous form, for a severe and prognostically unfavourable form of primary congenital glaucoma (PCG). This type of PCG has been previously demonstrated to be extremely frequent in the population of Gypsies (Roms) in Slovakia. In this study, all 33 PCG Gypsy patients examined were found homozygous for this particular mutation, and among 101 unrelated healthy screened subjects from the Gypsy ethnic community, almost 14% of mutation carriers were identified. The test sugesed here makes it possible to perform a direct DNA-based prenatal diagnosis of PCG in the families at risk, as well as to screen for gene carriers.

Aryl Hydrocarbon Hydroxylases↗
PubMed1997

Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal.

OBJECTIVE: To determine the etiology for recurrent 46,XY sex reversal in a family with two Swyer siblings. DESIGN: Deoxyribonucleic acid (DNA) from peripheral lymphocytes and sperm were analyzed for duplication of the dosage sensitive sex locus (DSS) and for mutations in sex-determining region on Y (SRY). SETTING: An academic teaching hospital. PATIENTS: A family consisting of mother, father, and five phenotypic daughters, of which two were 46,XY sex-reversed females. INTERVENTION: Deoxyribonucleic acid (DNA) extraction, polymerase chain reaction (PCR), Southern blotting, dosage densitometry, single-strand conformation polymorphism (SSCP), and sequencing. MAIN OUTCOME MEASURE: Comparison of control and subject DNA. RESULTS: Deoxyribonucleic acid (DNA) analysis of SRY in genomic DNA from the 46,XY sex-reversed siblings revealed identical missense mutations (T-->G) in both sisters. Analysis of the SRY gene in paternal lymphocyte and sperm DNA revealed mosaicism for wild and mutant (T-->G) SRY sequences. SRY analysis of sperm DNA also demonstrated the same mosaicism for the T-->G missense mutation. CONCLUSION: A postembryonic SRY mutation gave rise to paternal mosaicism for two distinct cell populations (SRY+/SRY-). The presence of a wild type SRY in the somatic cell line may account for a normal pattern of male sexual differentiation, whereas the presence of a mutated SRY in the germ line resulted in two 46,XY sex-reversed offspring. These results confirm a proposed mechanism for the condition of recurrent 46,XY sex-reversed females.

Adolescent↗
PubMed2002

The absence of factor V Leiden mutation in Malays with recurrent spontaneous abortions.

OBJECTIVES: The objectives of this study were to investigate the prevalence of factor V Leiden mutation in Malay women with recurrent spontaneous abortion and to clarify the contribution of the factor V Leiden mutation to recurrent miscarriages in these women. DESIGN: A prospective case control study between June 1999 and April 2000. SETTING: Hospital University Science of Malaysia, Kubang Kerian, Kelantan, and Maternal and Child Health Clinic, Pasir Mas, Kelantan, Malaysia. SAMPLES: A total of 46 Malay women with a history of three or more first or second trimester miscarriages were studied. The control group consisted of 46 parous women without obstetric complications. METHODS: Diagnosis of factor V Leiden mutation was made by examination of factor V Leiden allele product following Mnl I digestion of factor V Leiden alleles amplified by polymerase chain reaction. RESULTS: None of the 46 women with recurrent spontaneous abortion carried the mutation. Also, we found no subject carrying the factor V Leiden alleles in the control group. CONCLUSION: These results suggest that that there is no association between the factor V Leiden mutation and recurrent spontaneous abortion in the Malay population.

Abortion, Habitual↗
PubMed2004

c-KIT codon 816 mutation in a recurrent and metastatic dysgerminoma of a 14-year-old girl: case study.

Dysgerminomas are rare female germ-cell tumors that correspond histologically and immunohistochemically to seminomas. Analogous to seminomas, most dysgerminomas respond very well to cisplatin- or carboplatin-based chemotherapy and to radiotherapy. KIT tyrosine kinase is crucial for normal germ-cell development, and its expression is observed in the majority of seminomas and dysgerminomas. Recently, activating KIT mutations were described in a panel of male germ-cell tumors [5, 10]. All mutations were localized in exon 17, encoding the second tyrosine kinase domain. Because receptor tyrosine kinase KIT might also be involved in the pathogenesis of dysgerminomas, we studied the expression and mutational status of a pure dysgerminoma, which was sent to our department for diagnostic reasons. The tumor revealed an exon 17 D816 V mutation in the c-KIT gene and strong KIT expression was found immunohistochemically. Clinically, the tumor was highly aggressive and resistant to carboplatin-based chemotherapy. Our case raises the question of whether exon 17 c-KIT mutations might be involved in the pathogenesis of dysgerminoma and whether exon 17 KIT mutations may predict aggressive and chemotherapy-resistant behavior of dysgerminomas.

Adolescent↗
PubMed2006

Recurrent LRRK2 (Park8) mutations in early-onset Parkinson's disease.

Mutations in LRRK2 (leucine-rich repeat kinase 2) have been associated with autosomal dominant Parkinson's disease (PD) and cluster in several 3' exons of the gene. The majority of mutations have been detected in late-onset cases (age at onset >50 years). We screened 5 of the 51 exons of LRRK2 that previously have been reported to harbor mutations in 98 early-onset and 42 late-onset PD patients. We identified two mutations (c.4321C>T, c.6055G>A) in three early-onset patients. Screening of an additional 220 early-onset PD patients for these mutations revealed another mutation carrier. In conclusion, LRRK2 mutations need to be considered also in early-onset PD.

Adult↗
PubMed1998

Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online.

We used the single strand conformation polymorphism (SSCP) method to investigate 13 apparently unrelated Spanish patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequences of the low density lipoprotein (LDL) receptor gene. We found 16 aberrant SSCP patterns, and the underlying mutations were characterized by DNA sequencing. Five novel missense mutations, Q71E, C74G, C95R, C281Y and D679E, and one nonsense mutation, Q133X, were identified. We also found six missense mutations, S156L, D200Y, D200G, E256K, T413K and C646Y, and one stop codon mutation, W(-18)X, that were previously described in patients from other populations. A new frameshift mutation, 2085del19, was found in one patient. We also identified three splicing mutations; two of them are novel mutations, 1706-10G->A and 2390-1G->A, and the other one has been reported recently, 313+1G->C. Four patients were found to carry two different mutations in the same allele: Q71E and 313+1G->C; C95R and D679E; W(-18)X and E256K, and C281Y and 1706-10G->A. Our results demonstrate that there is a broad spectrum of mutations in the LDL receptor gene in the Spanish population.

DNA Mutational Analysis↗
PubMed1999

Mutation analysis of iduronate-2-sulphatase gene in 24 patients with Hunter syndrome: characterisation of 6 novel mutations. Mutation in brief no. 249. Online.

Hunter syndrome is a rare, X-linked, recessively inherited disease affecting approximately 1 in 132,000 males. The disease is caused by the inability to degrade dermatan sulphate and heparan sulphate due to mutations in the iduronate-2-sulphatase gene (IDS). The mutations causing the disorder are heterogeneous, ranging from small micro-lesions to gross deletions and inversions. We have screened DNA samples from a panel of 24 unrelated Hunter syndrome patients and have identified mutations in 16 individuals. Six mutations represent novel changes in the gene and these include two single base deletions (1264DC and 1632/3DT); two single base insertions (776/8insC and 1082insT); and two missense mutations--Y264N (914T-->G) and Q465P (1518A-->C). An additional two missense mutations and one splice site alteration identified in this study have been described previously. Southern analysis revealed complete or partial gene deletions in a further 7 patients.

DNA Mutational Analysis↗