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PubMed2004

Cystic fibrosis mutation screening before assisted reproduction.

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians, with a reported incidence of one in 2500. In 97-98% of men with CF, a congenital bilateral absence of the vas deferens (CBAVD) blocks the transport of spermatozoa from testicular or epididymal structures to the outer genital tract, resulting in azoospermia. Abnormalities in semen parameters have also been identified in males with CF. Around 10% of obstructive azoospermia is congenital and is due to mutations the CF gene. It is therefore suggested that men who have CBAVD should be considered for CF screening prior to intracytoplasmic sperm injection (ICSI) treatment. Men with azoospermia of unknown origin should also be considered for screening. Couples requesting surgical sperm retrieval/ICSI should therefore be advised and counselled to bear an elevated risk for CF in their offspring. Counselling of these couples is vitally important in order to help them understand and cope with the diagnosis.

Cystic Fibrosis↗
PubMed1999

Mutation screening of the UBE3A/E6-AP gene in autistic disorder.

Previous reports of individuals with autistic disorder with maternal duplications of 15q11-q13, the Prader-Willi/Angelman syndrome region, suggest this area as a source of candidate genes in autistic disorder. Maternal truncation mutations in UBE3A, which encodes for E6-AP ubiquitin-protein ligase, have been shown to cause Angelman syndrome, which can also result from the absence of maternal chromosomal material from this region. Despite showing no evidence for imprinting in other tissues, this gene was recently discovered to be preferentially maternally expressed in human brain and expressed solely from the murine maternal chromosome in the hippocampus and cerebellar Purkinje cells, regions implicated in the neuropathology of autism. Based on this evidence, the coding region and a putative promoter region were sequenced in ten autistic subjects. Several polymorphisms were detected, but no evidence was found for a functional mutation. Evidence for likely altered regulation of UBE3A expression in maternal 15q11-q13 duplications suggests further investigation of the regulatory regions of this gene in autistic disorder.

Autistic Disorder↗
PubMed2003

Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.

The analysis of the FOXL2 gene (3q23) in a series of two families and two sporadic cases affected with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is presented. This study detected two novel FOXL2 mutations (missence and nonsens mutations) and confirmed the recurrence of a previously described duplication. Magnetic Resonance Imaging (MRI) of the orbit, in one family, showed absence or hypotrophy of the eyelid superior levator muscle suggesting a possible role of FOXL2 in the development of this extra-ocular muscle.

Adult↗
PubMed1999

Mutation screening of phenylketonuria in the Far East of Russia.

We analyzed mutant genotypes at the human phenylalanine hydroxylase (PAH) locus among phenylketonuria (PKU) patients in the Far East of Russia. A total of 60 variant alleles from 30 PKU families were analyzed for prevalent Caucasian mutations and restriction fragment length polymorphism/variable number of tandem repeats (RFLP/VNTR) haplotypes. Seventy-eight percent of all variant alleles carried six mutations. The most prevalent mutation was R408W (63%), with a haplotype background of 2.3. It also showed a very high degree of homozygosity (43%). The other five mutations (R158Q, R261Q, R252W, R261X, and IVS12nt-1) accounted for 1.7%-6.7% of all PKU alleles, and a single haplotype was associated with each genotype, except for R261Q. The genetic structure of PKU patients in the Far East of Russia seems to be relatively homogeneous, compared with that in the other Slavic and Oriental populations of surrounding countries. Prediction of a clinical phenotype and carrier detection will be feasible using DNA tests.

Child↗
PubMed1997

The use of capillary electrophoresis for point-mutation screening.

Advances in capillary electrophoresis technology over the past three years have been rapid. Capillary electrophoresis offers high-throughput, high-resolution, automatic operation and on-line detection with automatic data acquisition, and this has stimulated its application to the analysis of DNA mutations. Many different PCR-based DNA-mutation assays have been developed for unknown and known mutations. This article compares conventional PCR-based mutation-detection assays with the methods developed for use with capillary electrophoresis. Future trends for mutation detection using capillary electrophoresis are also assessed, with a special emphasis on totally integrated, microchip capillary-electrophoresis-based mutation-detection systems.

DNA↗
PubMed2001

Mutation screening of the c-MYB negative regulatory domain in acute and chronic myeloid leukaemia.

Over-expression of the c-myb gene and expression of activated forms of myb are known to transform haemopoietic cells, particularly cells of the myeloid lineage. Truncations or mutations that disrupt the negative regulatory domain (NRD) of the Myb protein confer an increased ability to transform cells. Although it has proved difficult to link mutations in c-MYB to human leukaemia, no studies investigating the presence of mutations within the c-MYB NRD have been reported. Therefore, we have performed mutational analysis of this region, using polymerase chain reaction-single-stranded conformation polymorphism and sequence analysis, in 26 patients with acute or chronic myeloid leukaemia. No mutations were detected, indicating that mutation of this region of the Myb protein is not common in the pathogenesis or progression of these diseases.

Acute Disease↗
PubMed2006

Mutation screening of the peropsin gene, a retinal pigment epithelium specific rhodopsin homolog, in patients with retinitis pigmentosa and allied diseases.

PURPOSE: To investigate the peropsin gene (RRH), encoding a retinal pigment epithelium homolog of the rod-expressed opsin (rhodopsin), for the presence of pathogenic mutations causing retinitis pigmentosa (RP) or other retinal degenerations. METHODS: All seven exons composing the RRH open reading frame and the immediate intron sequences were analyzed by direct nucleotide sequencing of 613 patients with forms of retinal degeneration. RESULTS: One patient with retinitis punctata albescens was a heterozygote with the missense change Cys98Tyr (TGT>TAT, c.293G>A). This change affects the homologous residue that is the target of the rhodopsin mutation Cys110Tyr, a reported cause of dominant RP. Unfortunately, none of the patient's relatives were available for a segregation analysis to determine if this change is unambiguously associated with disease. No definite pathogenic mutation was found in any of the other 612 patients who were evaluated. CONCLUSIONS: The Cys98Tyr is a possible cause of retinitis punctata albescens, although this conclusion is tentative because the change was found in only one patient. Our results indicate that the peropsin gene is not a common cause of RP or some related retinal degenerations, at least in the set of patients we analyzed.

Cysteine↗
PubMed2006

Molecular and genomic studies of IMMP2L and mutation screening in autism and Tourette syndrome.

We recently reported the disruption of the inner mitochondrial membrane peptidase 2-like (IMMP2L) gene by a chromosomal breakpoint in a patient with Gilles de la Tourette syndrome (GTS). In the present study we sought to identify genetic variation in IMMP2L, which, through alteration of protein function or level of expression might contribute to the manifestation of GTS. We screened 39 GTS patients, and, due to the localization of IMMP2L in the critical region for the autistic disorder (AD) locus on chromosome 7q (AUTS1), 95 multiplex AD families; however, no coding mutations were found in either GTS or AD patients. In addition, no parental-specific expression of IMMP2L was detected in somatic cell hybrids containing human chromosome 7 and human cell lines carrying a maternal uniparental disomy for chromosome 7 (mUPD7). Despite the fact that no deleterious mutations in IMMPL2 (other than the inverted duplication identified previously) were identified in either GTS or AD, this gene cannot be excluded as a possible rare cause of either disorder.

Autistic Disorder↗
PubMedDate not supplied

CAG repeat length analysis and mutation screening of the androgen receptor gene in Japanese men with idiopathic azoospermia.

Because androgens are required for normal spermatogenesis, we are investigating abnormalities in the androgen receptor as a possible cause of impaired spermatogenesis in patients with idiopathic male infertility. The CAG repeat length in exon 1 and mutations of the androgen receptor gene were studied in 30 men with idiopathic azoospermia and in 51 fertile men. In men with azoospermia, plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were measured and testicular biopsies were performed. The CAG repeat length ranged from 19 to 30 (mean 23.4 +/- 2.9) and from 17 to 28 (mean 23.7 +/- 3.2) in men with azoospermia and in controls, respectively. There was no significant difference between the 2 groups. In men with azoospermia, the Johnsen testicular biopsy score negatively correlated with plasma FSH (P < .01). However, the Johnsen testicular biopsy score did not correlate with plasma LH and testosterone levels. The CAG repeat length did not correlate with the Johnsen testicular biopsy score, or with plasma concentrations of LH, FSH, and testosterone. No abnormalities in the androgen receptor gene were detected. These facts suggest that the CAG repeat length and alterations in the androgen receptor gene are not associated with the etiology of idiopathic azoospermia.

Adult↗
PubMed2003

Mutation screening and association study of the UBE2H gene on chromosome 7q32 in autistic disorder.

Autistic disorder is a severe neurodevelopmental disorder most probably caused by a complex interaction of genetic factors. Several genomewide scans identified multipoint LOD score peaks in region 7q32. In this region, UBE2H encodes an E2 enzyme of the ubiquitin-dependent proteolytic system. Mutations in another member of this system, the UBE3A gene, cause Angelman syndrome. The participation of E2 (ubiquitin-conjugating enzymes) or E3 (ubiquitin ligases) enzymes in neural development recently emerged. Given its physical location and function, we examined UBE2H as a candidate for involvement in autistic disorder. We confirmed by reverse transcription-polymerase chain reaction that the UBE2H gene was expressed in the rat and the human central nervous system. The rat UBE2H and human UBE2H deduced amino acid sequences are identical. We screened the seven exons of the UBE2H gene in autistic patients using single-strand conformation analysis. We observed a silent A-->G transition at position 336. A case-control association study was performed using this A/G polymorphism. A significant association was found between the G allele and a subgroup of autistic patients with developmental quotient higher than 30 (P=0.004). Although further studies are required, these results suggest that the UBE2H gene could be one of the 7q-susceptibility loci for autistic disorder.

Autistic Disorder↗
PubMed2002

Molecular analysis, mutation screening, and association study of adenylate cyclase type 9 gene (ADCY9) in mood disorders.

Chromosome 16p13 has been shown to display modest linkage signals for mood disorders in a number of studies. An interesting candidate gene in this region is the adenylate cyclase (AC) type 9 gene (ADCY9). ACs are critical in neuronal signaling, and perturbation of brain AC activity has been reported in mood disorder postmortem brains. ACs may also act as targets of antidepressants. Two distinct length transcripts for the ADCY9 gene have been reported, but molecular mechanisms are unknown. To investigate the potential role of ADCY9 in mood disorders, we clarified alternative poly(A) sites for the two mRNA species, delineated the exon-intron structure, and screened the gene for genetic variants. The two transcripts encoded by ADCY9 shared the first 10 exons, but exon 11 was shorter in one of the mRNA species. Seven single nucleotide polymorphisms, including a missense mutation and one polymorphic microsatellite repeat in the 3'-UTR, were identified. However, a case-control study using the missense polymorphism, 2316A>G (Ile772Met), and the tetranucleotide repeat (TTTA)n showed no significant association with mood disorders in Japanese samples. The DNA polymorphisms detected in this study can be tested in other ethnic samples and/or other psychiatric diseases.

Adenylyl Cyclases↗
PubMed2000

Mutation screening of human 5-HT(2B)receptor gene in early-onset obsessive-compulsive disorder.

The serotonin receptor 2B gene (HTR2B; MIM 601122) is a pharmacological and positional candidate gene in early-onset obsessive-compulsive disorder. Sequences of a putative promoter region and splice regions were first elucidated, then sequenced along with HTR2B coding regions. Probands from seven families included in a previous genome scan in which one of the strongest linkage findings was to a region including HTR2B, along with two genomic DNA pools of 10 unrelated control subjects and 10 unrelated autism probands were screened. One single nucleotide polymorphism was found in intron 1, that may be useful as a marker in genetic linkage and association studies. It does not appear likely to affect splicing. No evidence for functional mutation was found in the sequenced regions of HTR2B.

5' Untranslated Regions↗
PubMed2006

Mutation screening in Chinese hypokalemic periodic paralysis patients.

Thyrotoxic periodic paralysis (TPP), familial periodic paralysis (FPP), and sporadic periodic paralysis (SPP) are the most common causes of hypokalemic periodic paralysis (hypoKPP). The patients present with similar clinical features characterized by episodic attacks of muscle weakness and a decrease in blood potassium. Mutations in the gene encoding the voltage-sensor coding regions of the skeletal muscle sodium channel gene (SCN4A) and the alpha-1 subunit of the skeletal muscle calcium channel gene were analyzed in 23 Chinese hypoKPP patients, including 1 FPP pedigree, 14 TPP patients, and 8 SPP patients. In addition, R83H mutation of the potassium channel subunit gene which was originally published as periodic paralysis mutation was also analyzed. A heterozygous CGT-TGT mutation at codon 672 in SCN4A gene was identified to segregate with the disease in the FPP family. Mutations in these regions were excluded in those patients with SPP and TPP. The results suggest that a likely genetic basis for FPP does not contribute to TPP and SPP, despite close similarities among FPP, TPP, and SPP.

Adult↗