Hereditary Fructose Intolerance: Functional Study of Two Novel ALDOB Natural Variants and Characterization of a Partial Gene Deletion

被引:18
作者
Esposito, Gabriella [1 ,2 ,3 ]
Imperato, Maria Rosaria [2 ]
Ieno, Luigi [1 ,2 ]
Sorvillo, Rosa [1 ,2 ]
Benigno, Vincenzo [4 ]
Parenti, Giancarlo [5 ]
Parini, Rossella [6 ]
Vitagliano, Luigi [7 ]
Zagari, Adriana [2 ,8 ,9 ]
Salvatore, Francesco [1 ,2 ,3 ]
机构
[1] Univ Naples Federico II, Dipartimento Biochim & Biotecnol Med, I-80131 Naples, Italy
[2] CEINGE Biotecnol Avanzate SCarl, Naples, Italy
[3] IRCCS Fdn SDN, I-80143 Naples, Italy
[4] Osped S Giovanni di Dio, Unita Operat Pediat, Agrigento, Italy
[5] Univ Naples Federico II, Dipartimento Pediat, I-80131 Naples, Italy
[6] Osped San Gerardo, Pediat Clin, Monza, Italy
[7] CNR, Ist Biostrutture & Bioimmagini, I-80125 Naples, Italy
[8] Univ Naples Federico II, Dipartimento Sci Biol, Sez Biostrutture, I-80131 Naples, Italy
[9] Univ Naples Federico II, CNISM, I-80131 Naples, Italy
关键词
missense mutations; ALDOB kinetic analysis; ALDOB molecular modeling; intragenic deletion; HFI molecular diagnosis; HFI molecular epidemiology; ALDOLASE-B-GENE; MUSCLE FRUCTOSE-1,6-BISPHOSPHATE ALDOLASE; C-TERMINAL REGION; MOLECULAR-BASIS; MUTATIONS; MUTANT; IDENTIFICATION; SUBSTRATE; POPULATION; PREVALENCE;
D O I
10.1002/humu.21359
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease caused by impaired functioning of human liver aldolase (ALDOB). At least 54 subtle/point mutations and only two large intragenic deletions have been found in the ALDOB gene. Here we report two novel ALDOB variants (p.R46W and p.Y343H) and an intragenic deletion that we found in patients with suspected HFI. The residual catalytic activity of the recombinant p.R46W and p.Y343H variants toward F1P was particularly altered. We also characterized a large intragenic deletion that we found in six unrelated patients. This is the first report of six unrelated patients sharing the same ALDOB deletion, thus indicating a founder effect for this allele in our geographic area. Because this deletion involves ALDOB exon 5, it can mimic worldwide common pathogenic genotypes, that is, homozygous p.A150P and p.A175D. Finally, the identification of only one ALDOB mutation in symptomatic patients suggests that HFI symptoms can, albeit rarely, appear also in heterozygotes. Therefore, an excessive and continuous fructose dietary intake may have deleterious effects even in apparently asymptomatic HFI carriers. Hum Mutat 31:1294-1303, 2010. (c) 2010Wiley-Liss, Inc.
引用
收藏
页码:1294 / 1303
页数:10
相关论文
共 55 条
[1]   Hereditary fructose intolerance [J].
Ali, M ;
Rellos, P ;
Cox, TM .
JOURNAL OF MEDICAL GENETICS, 1998, 35 (05) :353-365
[2]  
ALI M, 1993, Q J MED, V86, P25
[3]  
ALI M, 1995, AM J HUM GENET, V56, P1002
[4]  
ALI M, 1994, HUM MOL GENET, V3, P203
[5]   NULL ALLELES OF THE ALDOLASE-B GENE IN PATIENTS WITH HEREDITARY FRUCTOSE INTOLERANCE [J].
ALI, M ;
TUNCMAN, G ;
CROSS, NCP ;
VIDAILHET, M ;
BOKESOY, I ;
GITZELMANN, R ;
COX, TM .
JOURNAL OF MEDICAL GENETICS, 1994, 31 (06) :499-503
[6]  
ANTONORAKIS SE, 2000, GENETIC BASIS HUMAN
[7]   Product binding and role of the C-terminal region in class I D-fructose 1,6-bisphosphate aldolase [J].
Blom, N ;
Sygusch, J .
NATURE STRUCTURAL BIOLOGY, 1997, 4 (01) :36-39
[8]  
BROOKS CC, 1991, AM J HUM GENET, V49, P1075
[9]   A PARTIALLY ACTIVE MUTANT ALDOLASE-B FROM A PATIENT WITH HEREDITARY FRUCTOSE INTOLERANCE [J].
BROOKS, CC ;
TOLAN, DR .
FASEB JOURNAL, 1994, 8 (01) :107-113
[10]   A POSSIBLE CASE OF TRANSIENT HEREDITARY FRUCTOSE INTOLERANCE [J].
CATTOSMITH, AG ;
ADAMS, A .
JOURNAL OF INHERITED METABOLIC DISEASE, 1993, 16 (01) :73-77