Clinical features and genotype of adenine phosphoribosyltransferase deficiency in iceland.

The purpose of this study was to characterize the clinical, diagnostic, and prognostic features of adenine phosphoribosyltransferase (APRT) deficiency in Icelandic patients, as well as determine their genotype. Medical records of all known patients in Iceland were reviewed. Urinalysis and polymerase chain reaction-based DNA mutation analysis were performed in all patients, siblings, and living parents of index cases. Twenty-three individuals homozygous for type I APRT deficiency were identified in 16 families from 1983 to 1998. There were 12 males and 11 females, and the median age at diagnosis was 37 years (range, 0.5 to 62 years). Seventeen patients were index cases and 6 patients were diagnosed during screening of first-degree relatives. Eighteen patients had symptomatic disease, 15 of whom experienced nephrolithiasis; 4 patients had mild to moderate renal insufficiency, 1 patient had advanced renal failure, and 1 patient died of uremic complications. Six patients experienced recurrent urinary tract infections and 3 infants had a history of reddish-brown diaper stains. Five patients were asymptomatic; 3 of these patients were diagnosed during routine urinalysis and 2 patients were identified during family screening. Urinary 2,8-dihydroxyadenine crystals were detected in all cases, except for the patient who died of end-stage renal failure. All 23 patients were homozygous for the same mutation (D65V) in the APRT gene. Allopurinol therapy successfully prevented further stone formation and significantly improved renal function in most patients with renal insufficiency. Our results suggest that APRT deficiency may be more common than previously recognized and can lead to severe renal failure if left untreated.

[A mutation detection in a transcription factor for adipocyte development in children with severe obesity.].

OBJECTIVE: A substantial proportion of human obesity may be explained by genetic variability. Researchers have tried to identify the important genes in obesity with little sucsess. PPARg2 (peroxisome proliferator activated receptor g 2) is a transcription factor of the nuclear hormone receptor superfamily. It plays a key role in the developement and differentiation of adipocytes. Recently the mutation Pro115Gln in the PPARg2 gene was identified and shown to have a significant correlation with severe obesity. The actual prevalence and distribution of this mutation is not known. The aim of this study was to look for this mutation among Icelandic children suffering from severe obesity. MATERIAL AND METHODS: Thirty-five children and adolescents, aged 4-18, who have been diagnosed with severe obesity participated in the study. Eight parents and siblings aged 19-41 also participated. All study subjects had been obese since early childhood. Body mass index (BMI) was used to describe the phenotype of the subjects. The participants had a BMI of 28.0 to 52.2 kg/m(2). Genomic DNA was extracted from leucocytes. A 131 bp segment was amplified using polymerase chain reaction. The amplified product was digested with the restriction enzyme Hinc II, resolved on agarose gel and visualized under ultraviolet illumination after staining with ethidium bromide. To examine other mutations on the same 131 bp segment enzymatic mutation detection (EMD) was used. Finally the segments giving variable results using EMD were sequenced using the classic Sanger s method. RESULTS: The mutation Pro115Gln was not found in any of the specimens after analysis of the restriction fragment length polymorphism. The results of EMD indicated mutations or polymorphisms in three of the subjects but DNA sequencing failed to confirm these results. CONCLUSIONS: The mutation Pro115Gln or other genetic alternations within the exon examined do not appear to have a significant role in severe early - onset obesity in Icelandic children.

[Complete androgen insensitivity in an Icelandic family caused by mutation in the steroid binding region of the androgen receptor.].

INTRODUCTION: Androgen insensitivity syndrome (AIS) is a X-linked rescessive disorder characterized by impairment of the androgen-dependant male sexual differentiation. The cause of AIS is in most cases a mutation in the gene of the androgen receptor on the X chromosome. In this study we describe an Icelandic family with two girls with AIS. A search for mutations in the androgen receptor gene was performed in order to identify the genetical and molecular basis for AIS in this family. MATERIAL AND METHODS: Genomic DNA was isolated from two girls with complete AIS and their close relatives. PCR was used to amplify all eight exons of the androgen receptor gene of the two AIS girls and SSCP used to screen for mutations. DNA fragments showing abnormal SSCP pattern were subjected to nucleotide sequencing. PCR based diagnostic method was developed and used to detect the mutation causing AIS in the family. RESULTS AND CONCLUSIONS: Using SSCP and DNA sequencing a CGA to CAA missense mutation in exon 5 at codon 752 was identified. The mutation causes in an Arg to Gln amino acid substitution (R752Q mutation) in the ligand binding domain of the androgen receptor and a complete androgen insensitivity. Members of the family were genotyped using a PCR based method for identification of the mutant allele. The results strongly indicated a de novo mutation in a germ cell of the maternal grandmother, as the mutation was not found in her blood leucocytes. The diagnostic test provided a basis for genetic counselling for the family.

[Hereditary hearing impairment. Mutation analysis of connexin 26 and POU3F4 genes in Icelanders with nonsyndromic hearing impairment.].

AIMS: Mutations in the connexin 26 (Cx26) gene have recently been shown to be a major cause of hereditary nonsyndromic sensorineural hearing impairment in Caucasians. Studies indicate that approximately 10-30% of all childhood deafness are due to Cx26 mutations and the most frequently observed mutation is Cx26 35delG. Mutations in the POU3F4 are the most common cause of X-linked nonsyndromic hereditary hearing impairment. The aim of our study was to determine presence and type of Cx26 and POU3F4 mutations in an Icelandic cohort with nonsyndromic hearing impairment. MATERIAL AND METHODS: All 15 individuals participating in the study, fulfilled the criteria of severe congenital nonsyndromic hearing impairment of unknown cause and the hearing loss was documented by audiologic testing in a clinical facility. Eleven had a family history and four were sporadic cases. All exons of the Cx26 and POU3F4 genes were amplified using PCR and six pairs of primers. The amplified DNA fragments were screened for sequence variations using enzymatic mutation detection and the nucleotide sequence of fragments showing signs of variation was determined. RESULTS AND CONCLUSIONS: Using the methods described above four distinct sequence variations were detected in the Cx26 gene. The 35delG allele causing hereditary recessive hearing impairment was identified in one homozygous and one heterozygous individual. The heterozygous 35delG individual was also shown to carry the recessive allele 358-360delGAG (E). A missense mutation, 101Teth C (M34T), supposed to cause autosomal dominant form of hearing impairment with variable penetrance, was detected in one heterozygous individual. A novel sequence variation without known clinical significance, -63Teth G, was found in the 5'-noncoding sequence in one control sample. No mutations were detected in the POU3F4 gene.