Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene:: Haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients

被引:0
作者
Gort, L [1 ]
Coll, MJ [1 ]
Chabás, A [1 ]
机构
[1] Inst Bioquim Clin, Barcelona 08028, Spain
关键词
ARSA; metachromatic leukodystrophy; MLD; haplotypes; genotype-phenotype correlation;
D O I
10.1002/(SICI)1098-1004(1999)14:3<240::AID-HUMU7>3.0.CO;2-L
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Arylsulfatase A (ARSA) deficiency is the main cause of metachromatic leukodystrophy (MLD), a lysosomal disorder with no specific treatment. In view of the importance of genetic counseling, analyses of mutations and polymorphisms, including the ARSA pseudodeficiency allele, were carried out in 18 unrelated Spanish MLD patients, A systematic search allowed us to identify 100% of the alleles involving 17 different mutations, 12 of which are novel: G32S, L68P, R84W, P94A, G99V, P136S, W193X, H227Y, R288H, G308D, T327I, and IVS6-12C-->G. Two new polymorphisms, 2033C>T and 2059C>T, were identified in intron 6 which, in combination with two polymorphisms previously described (2161C>G and 2213C>G), gave rise to four different haplotypes in the control population. In addition, we also studied polymorphism 842G>T. Linkage disequilibrium was detected between mutations IVS2 + 1G-->A, D255H, and T327I and specific haplotypes, suggesting a unique origin for these mutations. Moreover, mutation T327I was always associated with the T allele of the new rare variant A210A (893C>T). The distribution of mutation D255H (frequency 19.4%) among patients with different MLD clinical presentation revealed a clear genotype-phenotype correlation paralleling that reported for mutation IVS2 + 1G-->A (frequency 25%). Among the novel mutations, only P136S and R288H occurred on a background of the ARSA pseudodeficiency allele. Screening 182 normal chromosomes identified a frequency of 8.8% of this allele; moreover, we identified two unrelated subjects with the polyA- mutation in the absence of the N350S mutation, and this infrequent haplotype reinforced the heterogeneity of conditions with ARSA deficiency. Hum Mutat 14:240-248, 1999. (C) 1999 Wiley-Liss, Inc.
引用
收藏
页码:240 / 248
页数:9
相关论文
共 30 条
[21]   A genotype-phenotype correlation between null-allele mutations in the ferrochelatase gene and liver complication in patients with erythropoietic protoporphyria [J].
Minder, EI ;
Gouya, L ;
Schneider-Yin, X ;
Deybach, JC .
CELLULAR AND MOLECULAR BIOLOGY, 2002, 48 (01) :91-96
[22]   21-Hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations [J].
Wang, Ruifang ;
Yu, Yongguo ;
Ye, Jun ;
Han, Lianshu ;
Qiu, Wenjuan ;
Zhang, Huiwen ;
Liang, Lili ;
Gong, Zhuwen ;
Wang, Lili ;
Gu, Xuefan .
STEROIDS, 2016, 108 :47-55
[23]   Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b) [J].
Eghbali, Maryam ;
Abiri, Maryam ;
Talebi, Saeed ;
Noroozi, Zahra ;
Shakiba, Marjan ;
Rostami, Parastoo ;
Alimadadi, Hosein ;
Najafi, Mehri ;
Yazarlou, Fatemeh ;
Rabbani, Ali ;
Modarressi, Mohammad Hossein .
ORPHANET JOURNAL OF RARE DISEASES, 2020, 15 (01)
[24]   Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b) [J].
Maryam Eghbali ;
Maryam Abiri ;
Saeed Talebi ;
Zahra Noroozi ;
Marjan Shakiba ;
Parastoo Rostami ;
Hosein Alimadadi ;
Mehri Najafi ;
Fatemeh Yazarlou ;
Ali Rabbani ;
Mohammad Hossein Modarressi .
Orphanet Journal of Rare Diseases, 15
[25]   Patients with a Wide Range of Disorders Related to WFS1 Gene Variants: Novel Mutations and Genotype-Phenotype Correlations [J].
Grzybowska-Adamowicz, Julia ;
Gadzalska, Karolina ;
Jakiel, Paulina ;
Juscinska, Ewa ;
Gorzadek, Monika ;
Skoczylas, Sebastian ;
Ploszaj, Tomasz ;
Jarosz-Chobot, Przemyslawa ;
Kowalska, Irina ;
Mysliwiec, Malgorzata ;
Szadkowska, Agnieszka ;
Zmyslowska, Agnieszka .
GENES, 2024, 15 (12)
[26]   Interstitial deletion of chromosome 12q: Genotype-phenotype correlation of two patients utilizing array comparative genomic hybridization [J].
Klein, OD ;
Cotter, PD ;
Schmidt, AM ;
Bick, DP ;
Tidyman, WE ;
Albertson, DG ;
Pinkel, D ;
Rauen, KA .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2005, 138A (04) :349-354
[27]   Metachromatic leukodystrophy: Subtype genotype phenotype correlations and identification of novel missense mutations (P148L and P191T) causing the juvenile-onset disease [J].
Qu, Y ;
Shapira, E ;
Desnick, RJ .
MOLECULAR GENETICS AND METABOLISM, 1999, 67 (03) :206-212
[28]   A positive genotype-phenotype correlation in a large cohort of patients with Pseudohypoparathyroidism Type Ia and Pseudo-pseudohypoparathyroidism and 33 newly identified mutations in the GNAS gene [J].
Thiele, Susanne ;
Werner, Ralf ;
Groetzinger, Joachim ;
Brix, Bettina ;
Staedt, Pia ;
Struve, Dagmar ;
Reiz, Benedikt ;
Farida, Jennane ;
Hiort, Olaf .
MOLECULAR GENETICS & GENOMIC MEDICINE, 2015, 3 (02) :111-120
[29]   Prosaposin Deficiency and Saposin B Deficiency (Activator-Deficient Metachromatic Leukodystrophy): Report on Two Patients Detected by Analysis of Urinary Sphingolipids and Carrying Novel PSAP Gene Mutations [J].
Kuchar, Ladislav ;
Ledvinova, Jana ;
Hrebicek, Martin ;
Myskova, Helena ;
Dvorakova, Lenka ;
Berna, Linda ;
Chrastina, Petr ;
Asfaw, Befekadu ;
Elleder, Milan ;
Petermoeller, Margret ;
Mayrhofer, Heidi ;
Staudt, Martin ;
Kraegeloh-Mann, Ingeborg ;
Paton, Barbara C. ;
Harzer, Klaus .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2009, 149A (04) :613-621
[30]   Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation [J].
Wang, Jiaping ;
Zhang, Qingping ;
Chen, Yan ;
Yu, Shujie ;
Wu, Xiru ;
Bao, Xinhua ;
Wen, Yongxin .
BMC MEDICAL GENETICS, 2018, 19