Mitochondrial dysfunction in congenital nephrotic syndrome

The molecular mechanisms maintaining the kidney glomerular filtration barrier remain poorly understood. Recent evidence suggests that mitochondrial dysfunction is a characteristic feature of kidney glomeruli in congenital nephrotic syndrome of the Finnish type (CNF). Here we searched for detailed functional evidence of mitochondrial lesion in CNF kidneys. We used histochemical and immunohistochemical methods, quantitative measurement of mitochondrial DNA, and superoxide production to characterize the mitochondrial function. The results unequivocally show down-regulation of mitochondria-encoded respiratory chain components, whereas the respective nuclearly encoded subunits were close to normal. These results give detailed evidence of distinct mitochondrial dysfunction and of the resulting abnormal production of reactive oxygen species in CNF and suggest a critical role for mitochondria in maintaining the glomerular permeability barrier.     

长QT综合征KCNH2基因S4区新移码突变L539fs/47的研究

目的 对1个先天性长QT综合征家系进行分子遗传学分析.方法 应用短串联重复序列(short tandem repeat,STR)连锁分析确定突变基因的位点,聚合酶链反应-单链构象多态性结合测序的方法 筛选KCNH2基因的突变.结果 先证者KCNH2基因在第7外显子存在19 bp的缺失,位于KCNH2基因编码序列1619～1637之间,同时突变基因的下游存在1个A1692G(CTA→CTG,L564L)多态位点,引起L539fs/47移码突变.突变基因来源于父亲,其兄弟为致病基因的携带者但未出现临床症状.结论 KCNH2基因的L539fs/47移码突变是新突变点,是引起本家系临床症状的原因.     

A novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation

Mutations of the gene coding for emopamil binding protein (EBP) can lead to deficient activity of 3-β-hydroxysteroid Δ(8), Δ(7) isomerase and are most commonly identified in. association with the X-linked dominant (male lethal) chondrodysplasia punctata (CDPX2), also known as Conradi-Hunermann syndrome. Our group has identified a hemizygous EBP mutation in males with a phenotype remarkable for Dandy-Walker malformation, cataracts, collodion skin and cryptorchidism. Additional findings of hydrocephalus, dysplasia of the corpus callosum, cardiovascular, craniofacial and skeletal anomalies were regularly seen in affected males and the family histories were supportive of an X-linked -recessive condition. The regularly reproducible constellation of cardinal features aligns very nicely with other disorders of sterol biosynthesis and is further distinguished by an absence of arty clinical manifestations in obligate carrier females. Biochemical analysis of blood from cases demonstrated markedly increased levels of 8(9)-cholestenol, and 8-dehydroeholesterol and a mildly increased level of 7-dehydrocholesterol; a similar pattern to what is seen in CDPX2. Sequence analysis of EJJP revealed a novel hemizygous missense mutation at position 141, predictive of a tryptophan to cysteine substitution (c.141G>T, p.W47C). The unaffected mothers were heterozygous for the c.141G>T mutation arid showed random X-inactivation pattern upon.     

A novel pathogenic MYH3 mutation in a child with Sheldon–Hall syndrome and vertebral fusions

Sheldon–Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non‐progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman–Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3‐related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3‐related disorders.

     

Distribution of renal integrin receptors and their ligands in congenital nephrotic syndrome of the finnish type

The aim of this study was to examine the distribution of 1 and v integrins (Ints) and some of their ligands in the kidneys of patients with congenital nephrotic syndrome of the Finnish type (CNF) and in controls using indirect immunofluorescence with monoclonal antibodies. The mesangial reactivity of Int 1 and Int 1 subunits was more variable and an increased glomerular reactivity with Int 3 and Int-6 antibodies was found in CNF kidneys than in controls. Int 2 subunit was either completely missing from or found in significantly lesser amounts in CNF kidney glomeruli. The immunoreactivity for Int v was more variable, fainter and also more granular in CNF samples than in control kidneys. The glomerular reactivity for Int 5 was more diffuse and weaker, and in sclerotic Bowman's capsules more intense in CNF kidneys than in controls. Immunoreactivity for Int 6 was restricted and was comparable in extent in CNF and control kidneys. Of the extracellular matrix components studied, the expression of EDAFn, EDBFn, OncFn, Ln 2 chain, Ln 1 chain and tenascin was increased. This is also seen in several glomerular diseases with inflammation and sclerosis. Immunoreactivity for vitronectin was decreased. Several differences were found in the intensity or location of the immunostaining for the 1 and v Ints and their ligands in CNF kidneys compared with controls, which have not been found in any other proteinuric disease. Disturbed Int expression pattern in CNF may specifically reflect the disturbance of glomerular function caused by the primary defect in this disease.     

A new hepatitis B virus vaccine escape mutation in a renal transplant recipient.

Surface antigen mutations of hepatitis B virus (HBV) may lead to immune escape and cause failure of immunization. In this report, the development of a chronic HBV infection in a vaccinated renal transplant recipient with pre-existing anti-HBs antibody is documented. The sequencing data showed that the HBV strain carried five amino acid substitutions in the major hydrophilic region of the S protein, one (sS143L) located at the "a" determinant. A commercial HBsAg assay failed to detect the mutant antigen.     

A novel PTPN11 mutation in LEOPARD syndrome

PTPN11 gene mutations are common to both patients with Noonan (NS) and LEOPARD syndrome (LS). So far only two recurrent mutations have been identified in LS patients by different research groups, i.e., Tyr279Cys and Thr468Met. In this work we describe the third PTPN11 mutation that has been found in a single LS patient. The mutation (c.1517A>C) substitutes a proline for a glutamine at amino acid 506 (Gln506Pro) in the phosphatase domain (PTP) of the PTPN11 peptide SHP2. This region is a mutation hotspot. Changes at amino acids 501 to 504 cause NS. Gln506Pro is predicted, by modeling analysis, to seriously disrupt the normal contacts between the regulating N-SH2 and the active PTP domains, leading to hyperactivity of the phosphatase. This report demonstrates that rarer mutations other than Tyr279Cys and Thr468Met can be found in LS patients and the need of screening the whole gene in those negative for the commonest mutations.     

Enamel renal syndrome: A novel homozygous FAM20A founder mutation in 5 new Brazilian families

Enamel renal syndrome (ERS) is a rare autosomal recessive disorder not fully characterized. Here we investigated ERS characteristics in 11 patients from 5 Brazilian families through clinical examination, imaging, renal ultrasonography, laboratory tests and DNA sequencing. The patients' age ranged from 6 to 25 years-old, and the presence of hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis were common findings to all patients. Only 4 patients showed abnormal laboratory tests (vitamin D, parathyroid hormone, phosphate, calcium). Intellectual disability and renal cysts were present in 2 patients each. Biallelic loss of function mutation in FAM20A gene, characterized by one base pair deletion in exon 11, resulting in a frameshift replacing a glutamine at codon 483 for a lysine and terminating at position 24 [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect. Our results reinforce the distinct orofacial features of ERS, which are the clue for kidney examination and genetic testing. Early diagnosis is essential to minimize the deleterious effects related to ERS. Here we report the largest series of patients with ERS in a same population, and describe, for the first time, a founder mutation for FAM20A.