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Biomedical subjects

P Wieacker

Publications and source records attributed to P Wieacker.

At least 37 records · Page 2Linked to original sources
PubMed1999

Frequency of CFTR gene mutations in males participating in an ICSI programme.

A higher prevalence of cystic fibrosis transmembrane regulator (CFTR) gene mutations has been suggested both in men affected by congenital aplasia of the vas deferens, and in individuals presenting with reduced sperm quality. In this case, an increased risk for offspring being affected by cystic fibrosis (CF) can be expected in couples who are planning to undergo intracytoplasmic sperm injection (ICSI), since most of the male partners suffer from infertility. In order to determine the risk for these couples more precisely, we offered them a test for the most frequent CF mutations prevalent in the German population. The frequency of mutations within the CFTR gene in the female group was in the same range as expected for the general population (six out of 150). In 10 out of 207 males tested, infertility could be explained by exogenous factors not related to CFTR. Among the remaining 197 males with idiopathic infertility, we detected 13 heterozygotes for a mutation within the CFTR gene. This slightly, but significantly (P = 0.014), elevated rate could indicate that infertile males have, compared with the general population, an increased risk of being a carrier of a CFTR gene mutation.

Cystic Fibrosis↗
PubMed1998

Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.

The Wilms' tumor gene WT1 plays a key role in genitourinary development and subsequent normal function. Homozygous mutations of WT1 can be found in approximately 15% of Wilms' tumors. Furthermore, somatic heterozygous loss of WT1 is known to lead to cryptorchidism and hypospadias in males. A much more severe phenotype is seen in patients with Denys-Drash syndrome which results from heterozygous dominant-negative mutations of the gene. Characteristic features are mesangial sclerosis with early kidney failure, varying degrees of gonadal dysgenesis and high risk of Wilms' tumors. Here we show that a related disease, Frasier syndrome, characterized by focal glomerular sclerosis, delayed kidney failure and complete gonadal dysgenesis, is probably caused by specific intronic point mutations of WT1 that preferentially affect a CpG dinucleotide. Disruption of alternative splicing at the exon 9 splice donor site prevents synthesis of the usually more abundant WT1 +KTS isoform from the mutant allele. In contrast to Denys-Drash syndrome, no mutant protein is produced. The splice mutation leads to an imbalance of WT1 isoforms in vivo , as detected by RT-PCR on streak gonadal tissue. Thus, WT1 isoforms must have quite different functions, and the pathology of Frasier syndrome suggests that especially gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform.

Alternative Splicing↗
PubMed1998

A new missense substitution at a mutational hot spot of the androgen receptor in siblings with complete androgen insensitivity syndrome.

Several mutations have been described in the human androgen receptor gene including constitutional mutations in androgen insensitivity syndrome, somatic mutations in prostate cancer and triplet expansions in Kennedy's disease (Gottlieb et al. 1997). Here we report on two siblings with complete androgen insensitivity and a novel missense mutation, D695V, in their androgen receptor gene. The two XY females are siblings of German descent and presented at the ages of 23 and 19 years, respectively, with typical clinical features of complete androgen insensitivity. We found both siblings to be hemizygous for a new adenine to thymine transversion at the second nucleotide of codon 695 within the fourth exon of the human androgen receptor gene. The resulting missense mutation D695V is located at the amino-terminal border of the ligand-binding domain of the androgen receptor. The aspartic acid residue at this position is highly conserved in the steroid binding domains of other members of the nuclear receptor family and has already been found to be the site of two other missense mutations associated with androgen insensitivity syndrome (Ris Stalpers et al. 1991, Hiort et al. 1996). Three of four reported subjects showed the complete androgen insensitivity phenotype, in accordance with the two siblings in our study. We suggest that the existence of three pathological amino acid substitutions for aspartic acid 695 most likely reflects the essential role of this residue for normal androgen receptor function in male sexual differentiation.

Adult↗
PubMed1998

[XY gonadal dysgenesis (Swyer syndrome) with gonadoblastoma].

This is a case report of 46 xy gonadal dysgenesis (Swyer-syndrome) with bilateral androgen producing gonadoblastoma in streak gonads in a 15-year-old patient. The presenting features were: hypergonadotrophic hypogonadism, male pseudohermaphroditism and virilisation. A hypoplastic uterus with normal looking Fallopian tubes and bilateral adnexal tumors were detected through laparoscopy. A laparotomy was performed and the streak gonads with bilateral gonadoblastoma were removed. This led to a normalisation of serum testosterone and serum beta-HCG levels and an amelioration of signs of virilisation. Uterus and fallopian tubes were conserved during the operation. A second look laparoscopy 6 months later showed no evidence of recurrent tumor. No mutation were found in the sex-determining gene (SRY) on DNA-screening using SSCP assay.

Adolescent↗
PubMed1997

A(870)E mutation of the androgen receptor gene in a patient with complete androgen insensitivity syndrome and Sertoli cell tumor.

In a 60-year-old woman with complete androgen insensitivity syndrome (CAIS) and Sertoli cell tumor, a germline mutation (A870E) in exon 8 of the androgen receptor (AR) gene could be detected. A sister of the patient was also affected by CAIS and developed a Sertoli cell tumor at age 56. The mutation has not been described so far and could be seen in a causal relationship with the development of this tumor.

Androgen-Insensitivity Syndrome↗
PubMed1997

Localization of the gene for Wieacker-Wolff syndrome in the pericentromeric region of the X chromosome.

The Wieacker-Wolff syndrome (WWS, MIM* 314580), first described clinically in 1985, is an X-linked recessive disorder. In earlier studies, linkage between the WWS gene and DXYS1 at Xq21.2 and DXS1 at Xq11 as well as AR at Xq12 was reported. Here we report on a linkage analysis using highly polymorphic, short terminal repeat markers located in the segment from Xp21 to Xq24. No recombination between the WWS locus and ALAS2 or with AR (z = 4.890 at theta = 0.0) was found. Therefore, the WWS locus was assigned to a segment of approximately 8 cM between PFC (Xp11.3-Xp 11.23) and DXS339 (Xq11.2-Xq13).

Centromere↗
PubMed1997

Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias.

The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels. The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown. Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. Co-expression of KvLQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac Iks current. We now show that IsK not only changes the kinetics of KvLQT1 currents, but also its ion selectivity. Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant-negative mechanism. By contrast, a JLN mutation truncating the carboxyterminus of the KvLQT1 channel protein abolishes channel function without having a dominant-negative effect. This fully explains the different patterns of inheritance. Further, we identified a novel splice variant of the KVLQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.

Amino Acid Sequence↗
PubMed1997

[Structure and chromosomal localization of human neurogranin gene].

A 12.5-kb DNA fragment containing the entire human neurogranin gene (hng) was isolated from the genomic phage library using the human neurogranin (hNG) cDNA as a probe. The gene consists of four exons and three introns. The first two exons include the nucleotide sequence that encodes the complete 78-amino acid sequence of neurogranin. It is shown that the genome organization of hug is essentially similar to that of the homologous rat neurogranin gene (rng). The hng gene has several potential transcription start sites, and the promoter region is characterized by the absence of the CCAAT and TATA boxes in the proximal region upstream from the transcription start sites. The 5'-flanking region of hng has a domain with multiple AT-rich motifs, which is similar to the region present nearly at the same position in the promoter of rng. It was shown by fluorescence in situ hybridization that hng is located on chromosome 11 in the region 11q23.3-q24.1.

Amino Acid Sequence↗
PubMed1996

[Disorder of 17 beta-hydroxysteroid dehydrogenase as the cause of hypergonadotropic hypogonadism in 2 siblings with primary amenorrhea].

We report on two sibs with deficiency of 17 beta-hydroxysteroid dehydrogenase. The diagnosis is based on clinical features and endocrine parameters. Main symptoms were hypergonadotrophic hypogonadism and male pseudohermaphroditism with only slight virilisation. Endocrine investigations including ACTH and hCG stimulation revealed reduced levels of estradiol and testosterone, but elevated concentrations of DHEAS and androstendione.

17-Hydroxysteroid Dehydrogenases↗
PubMed1996

Sex reversal in a child with the karyotype 46,XY, dup (1) (p22.3p32.3).

The karyotype 46,XY, dup(1) (p22.3p32.3) was found in a 10-year-old patient with sex reversal, mental retardation and multiple dysmorphic features. In other cases with duplication 1p but different breakpoints cryptorchidism and genital ambiguity have been observed suggesting the dosage effect of a locus in 1p involved in sex differentiation.

Abnormalities, Multiple↗
PubMed1993

Influence of steroid hormones on 5 alpha-reductase activity in female and male genital skin fibroblasts in culture.

The physiological regulation of 5 alpha-reductase (5 alpha R) as well as the complex pathogenesis of male and female androgenic disorders are still incompletely understood. Therefore, we examined the influence of various steroid hormones on the 5 alpha R activity in female and male genital skin fibroblasts in primary culture to test whether the 5 alpha R activity is identically regulated in genital skin samples of both sexes. Nine foreskin samples of male patients and 11 specimens of female genital skin were prepared and cultured as primary tissue cultures. After pre-incubation with various unlabeled steroids, [3H]-testosterone was added to the cultures and the 5 alpha R activity (conversion of testosterone to dihydrotestosterone) measured. (a) The pre-incubation of male foreskin fibroblasts with unlabeled androstenedione and androstandione both resulted in stimulation of 5 alpha R activity. Other unlabeled steroid hormones, including progesterone, testosterone, dihydrotestosterone, and estradiol had no significant effect on 5 alpha R activity. (b) In female genital skin fibroblasts, pre-incubation with testosterone also led to an increase in 5 alpha R activity, whereas pre-incubation with estradiol decreased 5 alpha R activity. None of the other unlabeled steroid hormones applied had significant effects. These data on male foreskin in culture suggest a physiologic regulatory mechanism of 5 alpha R activity independent of the concentration of the enzymatic substrate or product, whereas the results for the female genital skin suggest a cellular regulation of the androgen levels by the enzymatic substrate testosterone and a possible negative feedback mechanism of estrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Point mutation in the steroid-binding domain of the androgen receptor gene in a family with complete androgen insensitivity syndrome (CAIS).

An exonic single nucleotide substitution in the human androgen receptor gene (hAR) could be detected in an Italian family with two children affected by complete androgen insensitivity syndrome (CAIS), also called testicular feminization. This mutation leads to a guanine to adenine transition in exon 5, changing the sense of the codon from methionine (ATG) to valine (GTG). As this mutation abolishes a NcoI restriction site, a rapid test for the mutation can be performed by digestion of the polymerase chain reaction products with this enzyme. Previous results of indirect gene diagnosis in this family could be confirmed by this method.

Amino Acid Sequence↗
PubMed1992

[The normal vascularization of the female breast in Doppler ultrasound].

Specific Doppler-Ultrasound methods for the differentiation of benign and malignant lesions by measurement of abnormal flow, have been known for more than 10 years. We used this method also in many patients without pathological breast problems and found a high physiological variation of blood flow. As basic definition of normal flow, to be compared with patients under medical treatment of mastopathy, we studied flow variations during menstrual cycles in normal volunteers. In both breasts we measured the amount of vessels, average frequency shifts according to flow velocity and the sum of all Doppler shifts, as measurement of the overall vascularity. Between different individuals the range of Doppler shifts was between 500 and 1000 Hz. However, in individual subjects the variation was only between 50-200 Hz, average 100 Hz. We also found between contralateral breasts no remarkable difference in vascularity. Flow increased at the 10th day after onset of menstruation, in 9 cycles with ovulation and in 8 cycles with a lack of gestagen production. Dramatic flow increase occurred in one early pregnancy. It appears that influences of drugs can be controlled, after basic measurements of individual vascularity.

Adult↗