A De Novo novel mutation of the EDNRB gene in a Taiwanese boy with Hirschsprung disease.

Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR. All eight genes are involved in the early development of the enteric nervous system, and most act through two distinct biochemical pathways mediated by RET and EDNRB. Mutations in RET and EDNRB account for up to 50% and 5% of HSCR cases in the general population, respectively. Interaction between these two signaling pathways could modify RET expression and, therefore, HSCR phenotype. Here, we report the case of a 1-year-old Taiwanese boy who presented with abdominal distension since birth and bilious vomiting after feeding. HSCR (short-segment type) was diagnosed based on X-ray, lower gastrointestinal series and biopsy findings. Mutation analysis revealed a heterozygous T>C missense mutation in exon 1 of the EDNRB gene, that substitutes the highly conserved cysteine-90 residue in the extracellular domain of the G protein-coupled receptor with an arginine residue (C90R). No RET gene mutation was detected in this patient.     

Campomelic dysplasia without sex reversal in a Turkish patient is due to mutation Ala119Val within the SOX9 gene.

Campomelic dysplasia is a rare neonatal skeletal malformation syndrome mainly characterized by congenital bowing and angulation of long bones in combination with other skeletal and extraskeletal defects. Two thirds of karyotypic males exhibit male-to-female sex reversal. Point mutations within SOX9 in 17q24-25 or rearrangements upstream to SOX9 as well as a deletion of a complete gene, causing haploinsufficiency of the gene product, have been detected in some patients. Recurrent mutations appear to be rare and most mutations detected in campomelic dysplasia are family specific. Here, we report on a Turkish patient with a 46,XY karyotype affected by campomelic dysplasia without sex reversal. Sequencing the SOX9 gene revealed a heterozygous Ala119Val mutation in exon 1, coding for the highly conserved HMG-box of the gene. This mutation is not present in the parents' lymphocyte DNAs. The same mutation was recently reported in a patient with 46,XX karyotype. Additionally, our patient is homozygous for the common polymorphism c507C-->T, while both parents are heterozygous.     

FSH-receptor <Emphasis Type="Italic">Ala307Thr</Emphasis> polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women

Objective  

Herein we analyzed FSH-R polymorphism at position 307 aiming (a) to assess the prevalence of the three allelic variants (Ala307Ala, Ala307Thr and Thr307Thr) in relation to the type of ovary and (b) to clarify if the allelic variant could influence the responsiveness to exogenous FSH.     

The effect of the D1-C785T polymorphism in the type 1 iodothyronine deiodinase gene on the circulating thyroid hormone levels in Romanian women with preeclampsia. Association with the degree of severity and pregnancy outcome of preeclampsia

Aim: To investigate the biochemical and genetic thyroid status in women with preeclampsia by the determination of serum FT3 and FT4 levels in association with D1-C785T genotypes. Methods: We genotyped using PCR–RFLP methods 50 women with preeclampsia and 50 normotensive pregnant women. Results: FT3 levels (pg/ml, 2.63?±?0.56 vs. 2.91?±?1.41) were low, and FT4 levels (ng/dl, 1.11?±?0.3 vs. 0.88?±?0.14) were high in women with preeclampsia compared to normal pregnant women. The association with severe preeclampsia was stronger for the homozygous T/T genotype (OR 6.57, p?=?0.029). Women with preeclampsia with the D1-T785 mutated allele had lower FT3 levels (pg/ml, 2.31?±?0.81 vs. 3.04?±?0.39, p?<?0.001), higher FT4 levels (ng/dl, 1.32?±?0.87 vs. 0.84?±?0.24, p?=?0.009) than women with preeclampsia with the D1-C/C genotype. Significant decrease in serum FT3 levels in positive women with severe preeclampsia compared to women negative for this genetic variation (pg/ml, 1.59?±?0.74 vs. 2.77?±?0.23, p?=?0.003) was observed. Women with severe preeclampsia, positive for the mutated T785 allele, delivered at a significantly lower gestational age (31.75?±?3.69 vs. 38.66?±?3.21 weeks, p?=?0.035) neonates with a lower birth weight (1861.11?±?869.9 vs. 3500?±?424.26?g, p?=?0.023) compared to women negative for the same allele. Conclusions: Thyroid hormone levels and the D1-C785T polymorphism, alone or in combination, correlate with the severity of preeclampsia. The D1-C785T polymorphism influences the outcome of pregnancy in severe preeclampsia.     

Prenatal diagnosis in two families with autosomal, p47(phox)-deficient chronic granulomatous disease due to a novel point mutation in NCF1

OBJECTIVE: Prenatal diagnosis was required in two unrelated families with chronic granulomatous disease (CGD) patients who lacked expression of p47(phox) protein; thus a search for mutations in NCF1 was undertaken. METHODS: Gene scanning was applied to establish the relative number of coding and pseudo-NCF1 genes. PCRs specific for coding NCF1 cDNA and coding NCF1 exon-7 genomic DNA were devised. RESULTS: The normal 1:2 ratio of coding and pseudo-NCF1 genes was found in the patients. Sequencing of the RT-PCR product specific for mRNA from the coding NCF1 genes revealed a novel homozygous G579A mutation in both patients, changing the TGG codon for Trp193 into the TAG stop codon. This mutation was confirmed in genomic DNA. The parents of both patients were found to be heterozygotes for this mutation. In the chorionic villus DNA of the first family a heterozygous G579A mutation was found. Postpartum, functional NADPH oxidase tests were normal. In the second family, this mutation was present in homozygous form in the chorionic villus DNA. Following termination of the pregnancy, the diagnosis of p47(phox)-deficient CGD was confirmed on DNA extracted from fetal blood. CONCLUSION: This is the first report of prenatal diagnosis in p47(phox)-deficient CGD.