[Show abstract][Hide abstract] ABSTRACT: Multiple sulfatase deficiency is a rare autosomal recessively inherited lysosomal storage disorder characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The aim of this study was to explore the clinical manifestations, enzyme activities and SUMF1 gene mutations in two Chinese patients with multiple sulfatase deficiency.
One boy and one girl from two families were studied. Both patients presented with mental retardation, mild coarse facial features, a neurodegenerative course of disease with loss of sensory and motor function after 2 years of age, ichthyosis and skeletal abnormalities (kyphosis or/and scoliosis). Clinical characteristics indicate multiple sulfatase deficiency.Sulfatases activities in blood leucocytes, plasma or cultured fibroblast of the patients were measured.Genomic DNAs were extracted from peripheral blood leukocytes from the patients and their parents. All SUMF1 gene exons and intron-exon boundaries were amplified by PCR and subjected for direct sequencing.
In case 1, five sulfatases activities of blood leucocytes and four sulfatases of cultured skin-fibroblasts were analyzed.In case 2, three sulfatases activities of blood leucocytes were tested.Significantly decreased sulfatases activities confirmed the diagnosis of multiple sulfatase deficiency.On SUMF1 gene, c.793_794 insATG (p. P265X)/ c.1045C>T (p.R349W) in case 1 and c.451A>G (p.K151E)/ c.1046G>C (p.R349Q) in case 2 were detected, respectively. Three novel mutations c.793_794insAGT, c.1046G>C and c.451A>G were identified.
Multiple sulfatase deficiency usually results in multi-organ damage, especially neurologic, skeletal and skin.Sulfatases assay and SUMF1 gene analysis are necessary for the diagnosis. Two Chinese cases with multiple sulfatase deficiency were firstly reported. Three novel mutations were found.It should be considered that the mutation profile of SUMF1 gene in Chinese patients is different from other populations.
No preview · Article · Nov 2013 · Zhonghua er ke za zhi. Chinese journal of pediatrics
[Show abstract][Hide abstract] ABSTRACT: Wilson disease (WD) is an autosomal recessive inherited disease caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in 114 individuals of Chinese Han population living in north China who were diagnosed as WD. Totally, we identified 36 mutations and 11 single-nucleotide polymorphisms (SNPs), of which 14 mutations have never been reported previously and 5 were firstly described in Chinese. Among these, p.R778L (21.5%), p.A874V (7.5%) and p.P992L (6.1%) were the most frequent mutations. A genotype of p.L770L+p.R778L+p.P992L was the most frequent triple mutations and two pairs of mutations, p.L770L/p.R778L and p.A874V/p.I929V, were closely related. In addition, a database was established to summarize all ATP7B mutations, including those reported previously and those identified in this study. Popular algorithms were used to predict the functional effects of these mutations, and finally, by comparative genomics approaches, we predicted a group of mutation hot spots for ATP7B. Our study will broaden our knowledge about ATP7B mutations in WD patients in north China, and be helpful for clinical genetic testing.Journal of Human Genetics advance online publication, 13 December 2012; doi:10.1038/jhg.2012.134.
No preview · Article · Dec 2012 · Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: To investigate efficient diagnosis and treatment of 17α-hydroxylase (17OHD) deficiency by summarizing clinical characteristics of those patients.
From January 1983 to January 2010, 48 cases with 17OHD in Peking Union Medical College Hospital were studied retrospectively.
Among 48 patients with 17OHD, karyotype analysis showed, 12 cases with 46, XX and 36 cases with 46, XY. The 46, XX karyotype and 46, XY karyotype with complete 17OHD had typical clinical presentation of amenorrhea[12/12, 100% (36/36)], no typical spontaneous puberty [12/12, 13.9% (5/36)], Hypertension [11/12, 100% (36/36)], hypokalemia [K(+): (2.6 ± 0.7), (2.8 ± 0.7) mmol/L], hypergonadotropin [follicle-stimulatinghormone (FSH): (51 ± 35), (79 ± 46) U/L, luteinizing hormone (LH): (27 ± 14), (49 ± 37) U/L], impaired production of sex hormones [testosterone (T): 0.003, 0.005 nmol/L; estradiol (E(2)): 26.86, 10.64 pmol/L], hyper-progesterone[ (P): (32 ± 15), (29 ± 23) nmol/L], impaired production of 17α-hydroxyprogesterone (17α-OHP)[(2.5 ± 1.1), (2.4 ± 1.7) nmol/L], ACTH hypersecreation (91.8, 114.0 pmol/L). ACTH stimulating test did not elevated in 17α-OHP and cortisol.
When patients with elevated basal serum levels of progesterone higher than that of ovulation period in addition to clinical symptoms, examination about 17OHD should be warranted.
No preview · Article · Jul 2012 · Zhonghua fu chan ke za zhi
[Show abstract][Hide abstract] ABSTRACT: Wang X, Zhang W, Shi H, Qiu Z, Meng Y, Yao F, Wei M. Mucopolysaccharidosis I mutations in Chinese patients: identification of 27 novel mutations and 6 cases involving prenatal diagnosis.
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease that results from the deficiency of α-l-iduronidase and is transmitted in an autosomally recessive manner. This report describes the first systematic screening for mutations in Chinese MPS I patients from mainland China, wherein we have summarized the phenotype/genotype correlation of the individuals in Chinese MPS I patients. Mutational analyses were performed in 57 unrelated Chinese MPS I patients. Overall, 105 mutant alleles were identified from a set of 41 different mutations. Notably, of these 41 mutations, 27 were novel mutations that consisted of 8 splicing mutations (c.1-2C>G, c.296+4G>A, c.300-1G>C, c.792+1G>C, c.973-4G>A, c.1189+5G>T, c.1402+1G>T and c.1402+2T>G), 1 nonsense mutation (p.W41X), 1 insertion (c.668-670ins GCG), 5 duplications (c.531dupT, c.657dupG, c.883dupC, c.1147dupG and c.1225dupG), 3 deletions (c.349delT, c.1593delG and c.1244-1271del27),1 nucleotide substitution c.2T>C and 8 missense mutations (p.H33P,p.F52L, p.G168V,p.T179R,p. E182D, p.L237R, p.L238R and p.L421P). The missense mutations p.A79V and p.L346R, which accounted for 16.7% (19/114) and 12.3% (14/114) respectively, were the common mutations in Chinese patients but were rare in the mutational profiles reported for other populations. These results indicate that Chinese MPS I patients may have a different mutational spectrum compared to those of other populations. Moreover, for the first time in China, molecular genetic methods were used for prenatal diagnosis of six cases in five families.
No preview · Article · Apr 2011 · Clinical Genetics
[Show abstract][Hide abstract] ABSTRACT: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from the deficiency in the lysosomal enzyme alpha-L-iduronidase (IDUA). The present study was conducted to identify IDUA gene mutations in attenuated (MPS I H/S and MPS I S) patients with MPS I in northern China.
Fourteen exons with adjacent intronic sequences of the IDUA gene in 11 MPS I patients were amplified by polymerase chain reaction (PCR), and the PCR products were sequenced directly and origin analysis was conducted.
Seven mutations were detected in the 11 MPS I patients, i.e., c.236 C to T (p. A79V), c.266 G to A (p.R89Q), c.265 C to T (p.R89W), c.532G to A (p.E178K), c.589G to A (p.G197S), c.1037T to G (p.L346R), and c.1877 G to A (p.W626X). All of them were known mutations. Six patients were homozygotes and 1 was heterozygote with nonsense mutation. In addition, 9 reported single nucleotide polymorphism (SNP) were detected, i.e., p.A8, p.A20, p.H33Q, p.R105Q, p.A314, p. A361T, p.T388, p.T410 and p.V454I.
The mutation spectrum of the IDUA gene in attenuated MPS I Chinese patients may be different from that in patients from other countries.
No preview · Article · Apr 2011 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics
[Show abstract][Hide abstract] ABSTRACT: Mucopolysaccharidosis type I (MPS I; MIM# 252800) is an autosomal recessive disease that results from the deficiency in the lysosomal enzyme α-L-iduronidase(IDUA). IDUA is one of the enzymes involved in degradation of glycosaminoglycans heparan sulphate and dermatan sulphate. The deficiency of IDUA leads to widespread accumulation of partially degraded mucopolysaccharides inside lysosomes, resulting in progressive cellular and multiorgan dysfunction. Up to now there is no definitely effective treatment for this disorder, therefore it is important to provide an accurate genetic diagnosis and prenatal diagnosis for the MPSI families. This study was conducted to detect IDUA gene mutation in patients with MPSIand make a definite diagnosis of homozygote or heterozygote and make first trimester prenatal diagnosis.
The 2 male probands included in this study were diagnosed as MPSI patients in Peking Union Medical College Hospital, case 1 was 2 years old and case 2 was 5 years old. Genomic DNA was extracted from leucocytes in the 2 patients and 2 mothers' cultured amniocytes. IDUA gene DNA sequence was amplified by polymerase chain reaction (PCR) and the PCR products were sequenced directly. Novel mutations were analyzed in 100 normal chromosomes.
The genotype of case 1 was p.L238R/c.883InsC, while of case 2 was c.531InsT/p.L346R. The fetal case 1 did not inherit the same pathogenic mutations as proband 1, the activity of the IDUA in amniocytes was 9.0 nmol/(h·mg pr). The fetal case 2 inherited the same pathogenic mutations with the proband, the genotype of fetal 2 was c.531InsT/p.L346R, the activity of the IDUA in amniocytes was 0.5 nmol/(h·mg pr).
Of the 4 mutations found in 2 MPS I patients, p. L238R, c.883InsC, c.531InsT were novel. The fetal case 1 was diagnosed as normal fetus while the fetus 2 was diagnosed as affected. The results of the two kinds of prenatal diagnostic methods were correspondent with each other.
No preview · Article · Apr 2011 · Zhonghua er ke za zhi. Chinese journal of pediatrics
[Show abstract][Hide abstract] ABSTRACT: To establish the multiple quantitative fluorescent polymerase chain reaction (QF-PCR) assay and evaluate its clinical application in prenatal diagnosis.
Totally 170 samples were collected between May 2008 and July 2009 in prenatal center of Peking Union Medical College Hospital; 123 of them were amniotic fluid, 9 were chorionic villous samples, 20 were fetal blood and 18 were villi from aborted fetuses. All samples were from women of Han nationality, with mean age of (34.1 ± 4.6) years old, and with mean gestational age of (19.6 ± 1.0) weeks. Cytogenetic cultures and karyotyping were made to every sample. Genomic DNA was extracted from the samples. The sequences of twenty short tandem repeat (STR) markers were designed according to the GenBank and references, including 6 STR markers in chromosome 21, 4 in chromosome 18, 4 in chromosome 13, 4 in chromosome X, 1 in chromosome Y and 1 universal marker in both X and Y chromosome. Each sample was amplified by two sets of multiple QF-PCR, which included 4 STR markers in each of 21, 18, 13 and sex chromosomes. If the result was uninformative, the third set of another 4 STR markers was added.
(1) Karyotyping. Cytogenetic analysis were made for all the 170 samples, 151 (89%) of which were normal, and 19 (11%) were abnormal. (2) QF-PCR assay. 167 (98%) samples were detected by QF-PCR. The results were obtained within 2 - 3 days after sampling. 134 samples were proved normal by QF-PCR, which was consistent with karyotyping. Among the 19 abnormal karyotype samples, 18 were detected as abnormal(eight were 21-trisomy, three were 18-trisomy)by QF-PCR. Among the 167 samples, 150 (90%) were detected using the first and second set of STR mixtures, and 3 (2%) were detected when the third set of STR was added. The remain 14 (8%) were uninformative. (3) The diagnostic efficiency of QF-PCR. The sensitivity of QF-PCR in prenatal diagnosis of common aneuploidities was 95%, the specificity, the false positive rate, the false negative rate, the positive predictive value and negative predictive value were 100%, 0, 5%, 100% and 99%, respectively. (4) Autosome and sex chromosome detection by QF-PCR. Among all the STR markers, D21S1270 and D21S1411 had the highest heterozygosities in chromosome 21, and DXS8377 had the highest in sex chromosome. The amplifications were stable.
Multiple QF-PCR assay is a valid alternative in rapid prenatal diagnosis of common chromosome aneuploidies. With high accuracy, it can be used for numerous sample test in large-scale laboratories.
No preview · Article · Jul 2010 · Zhonghua fu chan ke za zhi
[Show abstract][Hide abstract] ABSTRACT: To review and investigate the relationship of genotype and phenotype in Chinese patients with Gaucher disease (GD).
The samples were first screened for known mutations as reported previously in Chinese population. Long chain PCR and nested PCR were employed to amplify the segments of glucocerebrosidase functional gene in patients with unknown mutant alleles. The products of nested-PCR were subjected to DNA sequencing to detect the new mutations.
Forty kinds of mutations were detected in this panel of patients. The L444P mutation was the most common one accounting for 33.0% of mutant alleles. It was followed by F213I, N188S, V375L and M416V.
There are at least 40 mutations in Chinese GD patients. The spectrum of mutation is significantly different from that in Caucasians. 70% of mutant alleles have been characterized. It becomes feasible to make clinical and prenatal diagnoses through gene analysis.
No preview · Article · Dec 2009 · Zhonghua yi xue za zhi
[Show abstract][Hide abstract] ABSTRACT: To increase the success rate of prenatal diagnosis for classical phenylketonuria(PKU).
Three new short tandem repeat (STR) markers (PAH26, PAH32 and PAH9) within and surrounding phenylalanine hydroxylase(PAH) gene were selected for amplified fragment length polymorphism. The allele frequencies and polymorphism information contests (PIC) were determined in Chinese population.
The PIC of these three new STR markers was 0.518 (PAH26), 0.413 (PAH32) and 0.362 (PAH9) respectively. There was linkage disequilibrium between PAH9 marker and PAH-STR marker (TCTA)n in the intron 3 of PAH gene. The linkage phase of the mutant genes and the markers was established using the combination of PAH-STR, PAH26 and PAH32 in 95% families. Prenatal diagnosis was performed successfully with these markers in four cases.
By selecting or combining the three STR markers, the mutant genes could be distinguished from the normal allele in up to 95% of families with classical PKU.
No preview · Article · Sep 2007 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics