ABSTRACT
BACKGROUND: Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1). METHODS: We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis. RESULTS: We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions. CONCLUSIONS: Overall, 11% of subjects had AHI1 mutations, while approximately 2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype-phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.
Subject(s)
Abnormalities, Multiple/genetics , Adaptor Proteins, Signal Transducing/genetics , Brain Stem/abnormalities , Cerebellum/abnormalities , Kidney Diseases, Cystic/genetics , Mutation , Retinal Degeneration/genetics , Abnormalities, Multiple/diagnosis , Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Vesicular Transport , Amino Acid Motifs , Cohort Studies , Cytoskeletal Proteins , Female , Humans , Kidney Diseases, Cystic/diagnosis , Male , Membrane Proteins , Pedigree , Proteins/genetics , Retinal Degeneration/diagnosis , SyndromeSubject(s)
Abnormalities, Multiple/genetics , Duane Retraction Syndrome/genetics , Sequence Deletion/genetics , Transcription Factors/genetics , Base Sequence , Chromosome Breakage/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Male , Pedigree , Phenotype , Polymerase Chain Reaction , SyndromeABSTRACT
In this study, we investigated whether a TATA box polymorphism in the promoter of the UGT1*1 exon I, the most common detected DNA polymorphism in Gilbert's syndrome, is a contributory factor in unexplained pathologic or prolonged jaundice. 38 neonates who had unexplained pathologic jaundice, 37 neonates who had unexplained prolonged jaundice, and 35 healthy, nonjaundiced neonates were enrolled in the study. Genotypes were assigned as follows: 6/6 (homozygous for a normal allele bearing the sequence [TA](6)TAA), 7/7 (homozygous for an abnormal allele with the sequence [TA](7)TAA), and 6/7 (heterozygous with one of each allele). Of the 110 infants, 10 (9%) had 7/7, 51 (46%) had 6/7, and 49 (45%) had 6/6 genotype; the differences between the three groups were not statistically significant. Also no differences were observed among different genotypes and mean serum total bilirubin concentrations. In conclusion, we showed that TA 7/7 and TA 6/7 genotypes are not rare in our population and that the presence of these polymorphisms alone does not play a significant role in the etiology of unexplained pathologic or prolonged neonatal hyperbilirubinemia.
Subject(s)
Exons/genetics , Glucuronosyltransferase/genetics , Jaundice, Neonatal/genetics , Polymorphism, Genetic , Promoter Regions, Genetic/genetics , Alleles , Body Weight , Genotype , Gestational Age , Gilbert Disease/genetics , Heterozygote , Homozygote , Humans , Infant, Newborn , TATA Box/genetics , TurkeyABSTRACT
AIM: To clarify the role of maternal preeclampsia in jitteriness in preterm infants. METHODS: Sixteen premature infants of preeclamptic mothers were observed for occurrence of jitteriness and were compared with 32 premature infants born to normotensive women. RESULTS: Jitteriness was present in a significantly higher percentage (75 vs 6%) and persisted longer (4.5 +/- 5.6 vs 1.5 +/- 0.7 days) in the preterm infants of preeclamptic mothers. CONCLUSIONS: Maternal preeclampsia could be included among the pathological factors that cause jitteriness in preterm babies.
