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Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.

ABSTRACT: Niemann-Pick disease (NPD) types A/B are both caused by a deficiency of lysosomal acid sphingomyelinase and display autosomal recessive inheritance. These two types of the disease were described according to the presence (type A) or absence (type B) of neurological symptoms. We present a molecular analysis of 19 Spanish NPD A/B patients and two from Maghreb. Eight of the patients had type A and 13 had type B NPD. All mutant SMPD1 alleles were identified, including 17 different mutations, 10 of which were novel. The only frequent mutations in the 21 NPD patients were c.1823_1825delGCC (p.R608del) (38%) and c.1445C>A (p.A482E) (9%). Genotype-phenotype correlations were established for most of the mutations and, in particular, the p.R608del-type B association was confirmed. This mutation accounts for 61.5% of the mutant alleles in the type B subgroup of patients. Expression studies performed on six of the identified mutations confirmed them to be disease-causing due to their low enzyme activity. An allele with a mutation affecting a noncanonical donor splice site produced only aberrant mRNAs, corresponding to previously reported nonfunctional SMPD1 minor transcripts. This study is the first exhaustive mutational analysis of Spanish Niemann-Pick A/B disease patients.

SUBMITTER: Rodriguez-Pascau L

PROVIDER: S-EPMC2760245 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.

Rodríguez-Pascau Laura L Gort Laura L Schuchman Edward H EH Vilageliu Lluïsa L Grinberg Daniel D Chabás Amparo A

Human mutation 20090701 7

Niemann-Pick disease (NPD) types A/B are both caused by a deficiency of lysosomal acid sphingomyelinase and display autosomal recessive inheritance. These two types of the disease were described according to the presence (type A) or absence (type B) of neurological symptoms. We present a molecular analysis of 19 Spanish NPD A/B patients and two from Maghreb. Eight of the patients had type A and 13 had type B NPD. All mutant SMPD1 alleles were identified, including 17 different mutations, 10 of w ...[more]

PMID: 19405096

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Project description:BACKGROUND:Clinical observations and molecular analysis of the SMPD1 gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD) are scarce. METHODS:A cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations. RESULTS:The majority of our patients (25/27) were under 18 years of age. From the cohort group, eight (30%) fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four SMPD1 gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6), one termination mutation (p.Glu248X), and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu). Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried combinations of a mild mutation, c.4delC, on one allele and a severe mutation on the other allele. CONCLUSIONS:The Chinese population may have a comparably high incidence of sphingomyelinase-deficient Niemann-Pick disease type A. This study has identified some novel genotype and phenotype correlations in this rare and devastating disorder.

Dataset Information

Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.

Publications

Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.

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