A novel mutation of the MFN2 gene in a Chinese family with Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) is a group of clinically and genetically heterogeneous inherited neuromuscular disorders. At present, more than 30 loci have been reported to be associated with CMT disease; point mutations in the mitofusin 2 (MFN2) gene is one of the most common causes. We studied a Chinese family with CMT disease in which the phenotype of affected individuals varied, and the weakness condition of the distal legs in males, except the proband, was less severe than in females in this family. Linkage analysis and PCR sequencing revealed a missense mutation (NM_014874.3:c.1066 A>G) in the MFN2 gene, resulting in an animo acid substitution of threonine to alanine in condon 356 (Thr356Ala). This is a novel phenotype and mutation for CMT family.     

A novel mutation in EXT2 gene in a Chinese family with hereditary multiple exostoses

Hereditary multiple exostoses (HME) is an autosomal-dominant disorder characterized by the presence of bony outgrowths on the long bones. In this report, we describe a Chinese family with HME. Linkage analysis and mutation detection were performed. Linkage with the EXT2 was established in this family. A novel mutation, EXT2 c239-244delG, was identified. Mutation analysis in a family with HME allows for genetic counseling and prenatal diagnosis.     

A novel single-base deletion mutation of the RUNX2 gene in a Chinese family with cleidocranial dysplasia

We identified a disease-causing mutation of the RUNX2 gene in a four-generation Chinese family affected with cleidocranial dysplasia (CCD). For mutation analysis, the coding region of RUNX2 was sequenced with DNA from two patients and three unaffected family members. The RUNX2 mutation was investigated in 50 normal controls by denaturing high pressure liquid chromatography. A heterozygous single-base deletion (c.549delC) of RUNX2, which predicts a termination site at the 185th codon and leads to a stop in the runt domain of RUNX2 protein, was detected in both patients but not in the three unaffected members of the family. This mutation was also not found in 50 controls and has not been reported previously. We demonstrated that a novel mutation (c.549delC) of RUNX2 is associated with CCD in a Chinese family, adding to the repertoire of RUNX2 mutations related to CCD.     

A novel mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant cutaneous disorder, characterized by a mixture of hyperpigmented and hypopigmented macules mostly on the dorsal portions of the extremities. Pathogenic mutations have been identified in the double-stranded RNA-specific adenosine deaminase (DSRAD) gene. We studied a Chinese family that included four affected individuals with DSH phenotypes. PCR and direct sequencing were carried out to detect the entire coding region and exon-intron boundaries of the DSRAD gene. A novel nucleotide c.3002G>T missense mutation in the exon 11 of the DSRAD gene was detected in the proband and his father. This information expands the database on DSRAD gene mutations associated with DSH.     

一个遗传性胰腺炎家系中新发现的胰蛋白酶原基因突变

对1个遗传性胰腺炎(hereditary pancreatitis, HP)家系中6例成员和120例无亲缘关系健康人的胰蛋白酶原基因(protease serine 1, PRSS1)进行PCR扩增, 产物纯化后测序, 结合受检者的血清肿瘤标志物、糖尿病相关生化指标以及近亲属的一般临床资料进行分析。结果发现4例家系成员PRSS1基因3号外显子区136位碱基存在C→T杂合性突变, 他们的基因型表现为野生型与突变型杂合现象, 另外在先证者PRSS1基因的3号外显子区171位碱基还存在着一个同义突变点(C→T), 而对照组和家系其他成员中未发现此两种突变, 突变阳性患者表现为乳酸、糖基化血红蛋白和糖类肿瘤标志物(CA19-9、CA125)增高。因此, PRSS1基因3号外显子区136位碱基C→T杂合性突变与该家系遗传性胰腺炎有关, 是该家系中遗传性胰腺炎的遗传易感因素。     

A novel mutation in the SLCO2A1 gene in a Chinese family with primary hypertrophic osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO) is a rare monogenetic disease that closely mimics hypertrophic osteoarthropathy secondary to pulmonary or other pathology. The study of PHO provides an opportunity to understand both the pathogenesis of hypertrophic osteoarthropathy and the functions of the underlying genes. PHO is characterized by digital clubbing, periostosis and pachydermia. Two genes are known to be related to PHO: SLCO2A1 and HPGD. Here, we identified a recurrent heterozygous guanine-to-adenine transition at the invariant + 1 position of the donor site of intron 7 (c.940 + 1G > A) and a novel heterozygous missense mutation p.Asn534Lys (c.1602C > A) in exon 11 of SLCO2A1 in a Chinese young man with PHO. Identification of a novel genotype in PHO will provide clues to the phenotype–genotype relations and may assist not only in the clinical diagnosis of PHO but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling.     

A novel nonsense mutation of the sedlin gene in a family with spondyloepiphyseal dysplasia tarda

We report a new nonsense mutation in the human sedlin (SEDL) gene in a family with X-linked spondyloepiphyseal dysplasia tarda. A substitution of cytosine for adenine at nucleotide position 329 causing a nonsense mutation (S110X) in exon 6 was identified in the affected patient in the family.     

A novel mtDNA ND6 gene mutation associated with LHON in a Caucasian family

Leber's hereditary optic neuropathy (LHON) is a frequent cause of inherited blindness. A routine screening for common mtDNA mutations constitutes an important first in its diagnosis. However, a substantial number of LHON patients do not harbor known variants, both pointing to the genetic heterogeneity of LHON and bringing into question its genetic diagnosis. We report a familial case that exhibited typical features of LHON but lacked any of the common mutations. Genetic analysis revealed a novel pathogenic defect in the ND6 gene at 14279A that was not detected in any haplogroup-matched controls screened for it, nor has it been previously reported. This mutation causes a substantial conformational change in the secondary structure of the polypeptide matrix coil and may explain the LHON expression. Thus, it expands the spectrum of deleterious changes affecting ND6-encoding subunit and further highlights the functional significance of this gene, providing additional clues to the disease pathogenesis.     

A novel nonsense mutation of the GTP cyclohydrolase I gene in a family with dopa-responsive dystonia

We report a new nonsense mutation in the GTP cyclohydrolase I (GCH1) gene in a family with dopa-responsive dystonia. Two sisters and three children of the sisters are affected. The exons of the GCH1 gene were amplified by PCR and sequenced. The substitution of thymine for cytosine at nucleotide position 142 causing a nonsense mutation (Q48X) in exon 1 was identified in all of the five affected patients. There were three asymptomatic carriers of the mutation in the family.     

A novel missense mutation of the ATP2C1 gene in a Chinese patient with Hailey-Hailey disease

Benign familial chronic pemphigus (Hailey–Hailey disease, HHD; MIM 169600) is a rare autosomal dominant hereditary disorder characterized by pruritic vesicles, painful erosions and scaly erythematous plaques at the sites of friction and flexures. Mutations in ATP2C1, which encoding the human secretory pathway Ca²⁺/Mn²⁺-ATPase protein 1 (hSPCA1), have been identified as the pathogenic gene of HHD. We found a novel, distinct, heterozygous mutation during study of a Chinese patient with HHD. We identified a C→T transition at nucleotide 1235 (p.Thr352IIe), in exon 13 of ATP2C1. This observation would be useful for genetic counseling and prenatal diagnosis for affected families and in expanding the repertoire of ATP2C1 mutations underlying HHD.     

A novel splicing mutation in COL1A1 gene caused type I osteogenesis imperfecta in a Chinese family

Osteogenesis imperfect (OI) is a heritable connective tissue disorder with bone fragility as a cardinal manifestation, accompanied by short stature, dentinogenesis imperfecta, hyperlaxity of ligaments and skin, blue sclerae and hearing loss. Dominant form of OI is caused by mutations in the type I procollagen genes, COL1A1/A2. Here we identified a novel splicing mutation c.3207+1G>A (GenBank ID: JQ236861) in the COL1A1 gene that caused type I OI in a Chinese family. RNA splicing analysis proved that this mutation created a new splicing site at c.3200, and then led to frameshift. This result further enriched the mutation spectrum of type I procollagen genes.     

Identification of a recurrent insertion mutation in the LDLR gene in a Pakistani family with autosomal dominant hypercholesterolemia

Familial Hypercholesterolemia (FH) results in elevated levels of blood lipids including total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) with normal triglycerides (TG). This disease is one of the major contributors towards an early onset of coronary heart disease (CHD). The aim of the present study was to identify the genes responsible for causing FH in Pakistani population, for this purpose a large consanguineous FH family was selected for genetic analysis. Serum lipid levels, including TC, TG, LDL-C and high density lipoprotein cholesterol (HDL-C), were determined in patients and healthy controls. In order to find the causative mutation in this family, direct sequencing of the low density lipoprotein receptor (LDLR) gene was performed. In addition the part of the Apolipoprotein-B (APOB) gene containing the mutations R3500Q and R3500W was also sequenced. Affected individuals of the family were found to have raised TC and LDL-C levels. Sequencing revealed an insertion mutation (c.2416_2417InsG) in exon 17 of the LDLR gene in all the affected individuals of the family. Common FH causing APOB mutations were not present in this family. Heterozygous individuals had TC levels ranging from ~300–500 mg/dl and the only homozygous individual with typical xanthomas had TC levels exceeding 900 mg/dl. This is the first report of a known LDLR gene mutation causing FH in the Pakistani population. Despite a large heterogeneity of LDLR mutations there are still some common mutations which are responsible for FH throughout the world.