A novel mutation of TGF beta1 in a Chinese family with Camurati-Engelmann disease

Camurati–Engelmann disease (CED) [OMIM 131300] is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. It has been previously reported that CED is caused by mutations of the transforming growth factor beta 1 (TGFβ1) gene on chromosome 19q13.1–q13.3. Until now, seven mutations (LLL12-13ins, Y81H, R156C, R218C, R218H, H222D, C225R) in Australian, French, Belgian, Japanese, and European families have been reported and these data showed that there was no correlation between the nature of the mutations and the variability of the clinical manifestations. In this study, we found a Chinese family with CED and observed some intra-familial clinical variability and symptoms that became more severe with the age. A new TGFβ1 mutation (E169K) in exon 2 was identified in the Chinese family using polymerase chain reaction, direct sequencing analysis of PCR products and single-strand conformation polymorphism analysis. This mutation has not been previously reported in other countries in the world.     

Childhood course of renal insufficiency in a family with a uromodulin gene mutation

Mutations in the UMOD gene encoding uromodulin (Tamm-Horsfall glycoprotein) result in the autosomal dominant transmission of progressive renal insufficiency and hypo-uricosuric hyperuricemia leading to gout at an early age. The clinical appearance is characterized by renal insufficiency and gout occurring in the late teenage years, with end-stage kidney disease characteristically developing between 40 and 70 years of age. This report provides a long-term characterization of renal functional decline in three children from one family with a novel UMOD mutation (c.891T>G, p.C297W) who received allopurinol and a low protein diet. While renal functional decline is slow in individuals with UMOD mutations, it may appear early in life and be associated with marked hyperuricemia. Anemia was also noted in this family.     

Variable renal phenotype in a family with an INF2 mutation

Recent advances in the genetics of glomerular diseases have identified several causative genes of nephrotic syndrome and/or glomerular proteinuria. In 2010, the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, was identified as a novel causative gene of the autosomal dominant form of focal segmental glomerulosclerosis (FSGS). Here, we describe an additional familial case of FSGS associated with INF2 mutations. In the family, two siblings and their father had a heterozygous p.E220K mutation on INF2. This mutation manifested in these three individuals as incidentally detected proteinuria without overt nephrotic syndrome, but at different ages of 7, 9, and 30 years, respectively. Two siblings had nephrotic range proteinuria, and one developed end-stage renal disease 5 years later. Conversely, their father had a modest degree of proteinuria, and maintained normal renal function until age 47. A renal biopsy of one of the siblings revealed FSGS with irregular podocyte foot process morphology and focal glomerular basement membrane changes. This is the second paper describing a familial case of FSGS associated with INF2 mutations as well as intrafamilial phenotype variability.     

经典型Bartter综合征家系CLCNKB基因突变分析

目的 研究一个经典型Bartter综合征家系CLCNKB基因突变情况。 方法 提取该家系各成员患者外周血淋巴细胞基因组DNA,应用PCR扩增CLCNKB基因全部外显子及侧翼序列,并直接测序检测突变。选取50例无亲缘关系的健康人作为对照。 结果 在患者中检测到1个杂合（错义）突变,其第4号外显子,第482位碱基T→G突变,造成第161位氨基酸由亮氨酸变为精氨酸（482T>G,L161R）;家系中母亲为杂合突变（L161R杂合突变）,父亲未发现突变;查阅国内外文献及人类基因突变数据库,L161R未见报道,属新发现的突变。 结论 发现了一种新的CLCNKB基因突变：L161R。     

A novel stop mutation in the EDNRB gene in a family with Hirschsprung’s disease associated with Multiple Sclerosis

Purpose

We identified a girl with Hirschsprung’s disease (HSCR) whose mother and grandmother had HSCR associated with multiple sclerosis (MS). The aim of this study was to outline mutations in HSCR-related genes and MS susceptibility alleles in these three individuals.

Methods

The phenotypes were reviewed based on medical records. The three subjects had rectosigmoid HSCR verified with histopathology. The mother and grandmother fulfilled the McDonald criteria for MS. DNA was isolated from EDTA-preserved blood according to standard procedures. Exome sequencing aiming mainly at analyzing HSCR associated genes as well as Sanger sequencing for confirmation was performed.

Results

All affected individuals carry a novel heterozygous nonsense mutation in the EDNRB gene (c.C397T,p.R133X,refNM_000115), changing an arginine at position 133 into a premature stop codon. None of the subjects were homozygous for the HLA risk alleles for MS.

Conclusion

We report a novel non-sense EDNRB gene mutation in a girl with HSCR and her mother and grandmother with HSCR and MS. We propose that this EDNRB gene mutation plays a role in the etiology of HSCR and also makes the subjects susceptible to MS.     

Inheritance and spondylolisthesis: a radiographic family survey.

A radiographic suvey has been carried out of 147 first-degree relatives of forty-seven patients treated in Edinburgh for spondylolisthesis of the fifth lumbar vertebra; twelve patients had the dysplastic (congenital) type and thirty-five an isthmic defect. The survey identified 19 per cent of relatives with spondylolysis, and index patients with each type of spondylolisthesis had relatives with the opposite type. Index patients with the dysplastic form had a higher proportion of affected relatives (33 per cent) than had those with the isthmic type (15 per cent), but both figures were significantly in excess of the estimated frequency for the general population of under 1 per cent and 5 per cent respectively. Spina bifida occulta at the fifth lumbar or first sacral level or both, and lumbosacral segmental defects were commoner amongst all individuals with spondylolysis than amongst unaffected relatives (dysplastic form 94 per cent, isthmic type 32 per cent, unaffected relatives 7 per cent). However, there was no single instance of a neural tube defect (anencephaly, spina bifida with or without meningocele, other generalised vertebral anomalies or spinal dysraphism) amongst 826 first-, second- or third-degree relatives. It is concluded that the developmental defects of the vertebrae associated with spondylolysis are not aetiologically related to the neural tube defects. The one in three risk of spondylolysis to near relatives of patients with the dysplastic form of spondylolisthesis is emphasised in order that the deformity in their sibs and children can be recognised at any early age.     

Whole-exome sequencing identifies a potential TTN mutation in a multiplex family with inguinal hernia

Hernia - Inguinal hernia repair is one of the most common procedures in general surgery. Males are seven times more likely than females to develop a hernia and have a 27 % lifetime...     

RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease

BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.     

Functional consequences of a novel uromodulin mutation in a family with familial juvenile hyperuricaemic nephropathy

Background. Familial juvenile hyperuricaemic nephropathy (FJHN)is an autosomal-dominant disorder featuring hyperuricaemia,low fractional urate excretion, interstitial nephritis and chronicrenal failure. The responsible gene UMOD was recently identified.UMOD encodes for uromodulin or Tamm–Horsfall glycoprotein,the most abundant protein in normal urine. We encountered afamily with FJHN and identified a novel UMOD mutation in exon6. Methods. We sequenced the gene in all family members, identifiedthe mutation, and verified its presence in the affected members.We next performed functional studies of the mutant protein byimmunofluorescence and FACS analysis on transfected cells. Results. The mutation p.C347G (c.1039T>G) results in a conservedcysteine to glycine amino acid substitution in the uromodulinzona pellucida (ZP) domain. The cell studies showed that thenovel uromodulin mutation causes a delay in protein export tothe plasma membrane due to its retention in the endoplasmicreticulum. Conclusions. We describe the first reported mutation mappingin the ZP uromodulin domain. Our data provide further evidenceshowing why the excretion of uromodulin is reduced in this syndrome.     

Putative mutation of PKD1 gene responsible for autosomal dominant polycystic kidney disease in a Chinese family

Autosomal dominant polycystic kidney disease (ADPKD) is a common and severe renal disease. Mutations of PKD1 and PKD2 genes are responsible for approximately 85% and 15% of ADPKD cases, respectively. In the present study, PKD1 and PKD2 genes were analyzed in a large Chinese family with ADPKD using denaturing high‐performance liquid chromatography and DNA sequencing. A novel mutation, c.3623‐3624insGTGT in exon 15 of the PKD1 gene, was identified in all nine affected family members, but not in any unaffected consanguineous relatives or 100 unrelated controls. These findings suggest that the unique 4 bp insertion, c.3623‐3624insGTGT, in the PKD1 gene might be the pathogenic mutation responsible for the disease in this family.     

Novel heterozygous COL4A3 mutation in a family with late-onset ESRD

Thin basement membrane nephropathy (TBMN) and Alport syndrome (ATS) are genetically heterogeneous conditions characterized by structural abnormalities in the glomerular basement membrane (GBM). TBMN presents with hematuria, minimal proteinuria, and normal renal function. Although TBMN is an autosomal dominant disease (COL4A3 and COL4A4), ATS can be inherited X-linked (COL4A5), autosomal recessive, or autosomal dominant (both COL4A3 and COL4A4). The clinical course of TBMN is usually benign, whereas ATS typically results in end-stage renal disease (ESRD). Nevertheless, there is a broad spectrum of clinical phenotypes caused by mutations in COL4A3 or COL4A4. We report an Italian family who presented with hematuria and mild proteinuria. Mutational analysis showed a novel heterozygous mutation p.G291E in exon 15 of the COL4A3 gene. Many different mutations in COL4A3 and COL4A4 that cause TBMN have already been identified, but most genetic variability in these genes has been found to cause autosomal ATS. A valid genotype–phenotype correlation for TBMN or ATS is not yet known. Therefore, it is important to identify new mutations by direct sequencing to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy.     

Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene

BACKGROUND: We have recently identified a mutation in the uromodulin gene in a large family affected with hyperuricemia, gout, and renal failure. The purpose of this investigation is to provide a comprehensive characterization of the clinical findings of this syndrome in family members who had a mutation in the uromodulin gene. METHODS: An extended family suffering from hyperuricemia and gout was identified by a local practitioner. After consent was obtained, patients provided a directed clinical history and blood and urine specimens for chemical and genetic testing. All family members were tested for the presence of uromodulin gene mutations by direct DNA sequence analysis. The clinical and biochemical characteristics of family members carrying the affected mutation were then investigated. RESULTS: Thirty-nine family members were found to have an exon 5 uromodulin gene mutation (g.1966 1922 del), and 29 unaffected family members were identified. The cardinal clinical features in individuals with the uromodulin mutation included hyperuricemia, decreased fractional excretion of uric acid, and chronic interstitial renal disease leading to end-stage renal disease (ESRD) in the fifth through seventh decade. Women did not always develop hyperuricemia or gout, but still developed progressive chronic renal failure. CONCLUSION: Mutation of the uromodulin gene resulted in hyperuricemia, reduced fractional excretion of uric acid, and renal failure. Genetic testing will be required to definitively identify individuals suffering from this condition. We are interested in studying other families that may suffer from this condition and would appreciate any such referrals.     

Strumpell's disease in a family with hereditary focal segmental glomerulosclerosis

Strumpell's familial spastic paraplegia is a rare hereditary disease, clinically characterized by progressive disturbance of gait. Focal Segmental Glomerulosclerosis (FSGS) is a frequent glomerulopathy, with an extremely rare familial subtype. The cases of two brothers with Strumpell' s disease are reported, who also developed glomerular renal disease, most probably familial FSGS. The genetics of the two disorders, Strumpell's paraplegia and familial FSGS, are discussed, together with the possibility of a parallel transmission.     

A novel G472R mutation in a Turkish family with X-linked Alport syndrome

Alport syndrome (AS) is a hereditary disorder of progressive nephritis. Most cases are X-linked, but autosomal forms have been reported. The X-linked form is associated with mutations in the COL4A5 gene that encodes the α5 chain of type IV collagen. More than 200 mutations have been reported in X-linked AS. We report a novel 1616 G>A mutation resulting in glycine substitution to arginine at position 472 in a Turkish family with a severely affected man and several variably affected women. This is the first Turkish family in whom the molecular basis of the disease has been reported. Received: 16 December 1998 / Revised: 30 June 1999 / Accepted: 7 July 1999