Alternative titles; symbols
HGNC Approved Gene Symbol: SMPD1
SNOMEDCT: 39390005, 52165006; ICD10CM: E75.240, E75.241;
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38) : 11:6,390,474-6,394,996 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Niemann-Pick disease, type A | 257200 | Autosomal recessive | 3 |
| Niemann-Pick disease, type B | 607616 | Autosomal recessive | 3 |
Quintern et al. (1989) microsequenced 128 residues from acid sphingomyelinase (EC 3.1.4.12) purified from urine, synthesized oligonucleotide mixtures based on minimal codon redundancy, and used these to screen human fibroblast and placenta cDNA libraries. The findings demonstrated the presence of 2 distinct acid sphingomyelinase transcripts in both human fibroblasts and placenta, suggesting possible alternative processing of the mRNA. both transcripts were approximately 2.5 kb. By screened human placenta, testis, hepatoma, and retina cDNA libraries,
Schuchman et al. (1991) isolated SMPD1 transcripts, including the previously described type 1 and type 2 cDNAs, as well as a third cDNA. Functional studies showed that only the type 1 transcript encoded catalytically active functional human ASM. The type 1 cDNA encoded a 629-amino acid protein. Rodriguez-Pascau et al. (2009) noted that human ASM protein is synthesized as a 75-kD prepolypeptide, which is converted into a precursor form of 72 kD. The precursor is subject to 2 different processing events. A minor part is cleaved in the ER-Golgi complex, yielding a 57-kD form, whereas a major part is processed to a 70-kD mature form.
Using the SMPD1 cDNA as a probe, Schuchman et al. (1992) isolated the SMPD1 genomic region and determined the complete nucleotide sequence of the gene including 1,116 and 468 nucleotides upstream and downstream, respectively, from the coding region. They determined that the SMPD1 gene contains 6 exons. Exon 2 is unusually large and encodes 258 amino acids, or about 44% of the mature ASM polypeptide.
Da Veiga Pereira et al. (1991) demonstrated by Southern blotting of somatic cell hybrids that the SMPD1 gene maps to 11p15.1-p15.4, not to chromosome 17 as had been reported by Konrad and Wilson (1987). By in situ hybridization, da Veiga Pereira et al. (1991) refined the localization to 11p15.
By PCR-amplification detection assay of a mouse/hamster somatic cell hybrid panel, Horinouchi et al. (1993) mapped the orthologous gene in the mouse (Smpd1) to chromosome 7, in a region of well-known homology to distal 11p where the human gene is situated.
Suchi et al. (1992) demonstrated that the metabolic defect in cultured Niemann-Pick disease (see 257200) cells, which lack sphingomyelinase activity, could be corrected by retroviral-mediated transfer of human ASM cDNA.
Stress is believed to activate sphingomyelinase to generate ceramide, which serves as a second messenger in initiating the apoptotic response. The first conclusive evidence for this paradigm was provided by Santana et al. (1996) who showed that lymphoblasts from Niemann-Pick patients failed to respond to ionizing radiation with ceramide generation and apoptosis. These abnormalities could be reversed by restoring acid sphingomyelinase activity by retroviral transfer of human acid sphingomyelinase cDNA. Mice in which the gene had been knocked out also showed defects in radiation-induced ceramide generation and apoptosis in vivo. Comparison with p53 knockout mice suggested to Santana et al. (1996) that acid sphingomyelinase-mediated apoptosis and p53-mediated apoptosis are probably distinct and independent.
Garcia-Ruiz et al. (2003) studied the contribution of ASM in TNF-alpha (191160)-mediated hepatocellular apoptosis. They showed that selective mGSH (mitochondrial glutathione) depletion sensitized hepatocytes to TNF-alpha-mediated hepatocellular apoptosis by facilitating the onset of mitochondrial permeability transition. Inactivation of endogenous hepatocellular ASM activity protected hepatocytes from TNF-alpha-induced cell death. Similarly, ASM -/- mice were resistant in vivo to endogenous and exogenous TNF-alpha-induced liver damage. Targeting of ganglioside GD3 (601123) to mitochondria occurred in ASM +/+ but not in ASM -/- hepatocytes. Treatment of ASM -/- hepatocytes with exogenous ASM induced the colocalization of GD3 and mitochondria. Garcia-Ruiz et al. (2003) concluded that ASM contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the targeting of mitochondria by glycosphingolipids.
Grassme et al. (1997) provided evidence that acid sphingomyelinase mediates entry of Neisseria gonorrhoeae into nonphagocytic cells. Invasion of human mucosal cells by N. gonorrhoeae via the binding to heparan sulfate proteoglycan receptors is considered a crucial event of the infection. Using different human epithelial cells and primary fibroblasts, Grassme et al. (1997) demonstrated an activation of phosphatidylcholine-specific phospholipase C and ASM by N. gonorrhoeae, resulting in the release of diacylglycerol and ceramide. Genetic and/or pharmacologic blockade of ASM and phosphatidylcholine-specific phospholipase C caused inhibition of cellular invasion by N. gonorrhoeae. Complementation of ASM-deficient fibroblasts from Niemann-Pick disease patients restored N. gonorrhoeae-induced signaling and entry processes. Grassme et al. (1997) concluded that activation of phosphatidylcholine-specific phospholipase C and ASM is an essential requirement for the entry of N. gonorrhoeae into distinct nonphagocytic human cell types including several epithelial cells and primary fibroblasts.
Kirkegaard et al. (2010) demonstrated that the reduced ASM activity in cells from patients with Niemann-Pick disease A and B is also associated with a marked decrease in lysosomal stability, and that this phenotype could be effectively corrected by treatment with recombinant Hsp70 (140550). Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential cofactor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of ASM. The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (trp90 to phe), as well as the pharmacologic and genetic inhibition of ASM, effectively reverted the Hsp70-mediated stabilization of lysosomes. Kirkegaard et al. (2010) concluded that, taken together, their data opened exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.
Levran et al. (1991) identified a point mutation in the SMPD1 gene (607608.0001) in an Ashkenazi Jewish patient with type A Niemann-Pick disease (257200) and Levran et al. (1991) identified a 3-bp deletion in the SMPD1 gene (R608del; 607608.0002) in an Ashkenazi Jewish patient with type B Niemann-Pick disease (607616).
Takahashi et al. (1992) characterized 6 Niemann-Pick disease mutations (see 607608.0004-607608.0009) and concluded that small deletions or nonsense mutations that result in a truncated ASM polypeptide and missense mutations that render the enzyme noncatalytic cause type A Niemann-Pick disease, whereas missense mutations that produce a defective enzyme with residual catalytic activity cause the milder nonneuronopathic type B phenotype. Ida et al. (1996) identified 3 novel mutations in the SMPD1 gene in Japanese patients with type A and B Niemann-Pick disease.
Lee et al. (2003) investigated a kindred with type B Niemann-Pick disease resulting from heteroallelic (i.e., compound heterozygous) mutations in the SMPD1 gene (607608.0002 and 607608.0014) associated with low levels of HDL cholesterol. Both the index patient, a 47-year-old male, and his sister, who was 2 years younger, had hypertriglyceridemia; the sister also had severe premature coronary artery disease. By studying cellular cholesterol efflux in fibroblasts, Lee et al. (2003) found that, unlike patients with Tangier disease (205400), cholesterol efflux was normal under the experimental conditions used.
Rodriguez-Pascau et al. (2009) identified 17 different mutations in the SMPD1 gene, including 10 novel mutations (see, e.g., A482E; 608607.0016 and Y467S; 608607.0017), in 19 Spanish patients and 2 patients from Maghreb in Northern Africa with Niemann-Pick disease type A (8 patients) or type B (13 patients). The most common mutations were the R608del mutation, found in 38% of alleles, and the A482E mutation, found in 9% of alleles. The R608del mutation was always found in patients with type B disease. Functional expression studies of the mutant proteins in COS-7 cells showed decreased enzyme activity.
Imprinting
The basis of the variability between type A and type B NPD is poorly understood and does not always correlate with the individual SMPD1 mutations. In addition, some carrier individuals for ASM-deficient NPD have features of the disease (Lee et al., 2003), which is an unusual finding for an autosomal recessive disorder such as this. Rethy et al. (2000) described a patient with Beckwith-Wiedemann syndrome (BWS; 130650) who had approximately 30% of normal ASM activity in cultured skin fibroblasts. This 23-month-old child had a normal karyotype, which suggested uniparental disomy of paternal chromosome 11p15. Rethy et al. (2000) suggested that the SMPD1 gene might be imprinted, on the basis of the reduced ASM activity in this patient, the possibility of 11p15 uniparental disomy, and the fact that the SMPD1 gene has structural features common to other imprinted genes (Rethy, 2000). To assess imprinting at the SMPD1 locus, Simonaro et al. (2006) studied several heteroallelic patients with ASM-deficient NPD. They demonstrated that the SMPD1 gene is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus RT-PCR sequencing for several patients with NPD revealed preferential expression of 1 mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2-prime-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated.
Simonaro et al. (2006) identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed.
Complete sequencing of the Smpd1 gene in 2 mouse models of Niemann-Pick disease by Horinouchi et al. (1993) revealed no mutation, indicating that these are not models of either type A or type B Niemann-Pick disease. One of the models, spm/spm, was thought to be a model of type C Niemann-Pick disease (257220) and the other may be a model for either type C or type D (see 257220).
By homologous recombination in embryonic stem cells, Otterbach and Stoffel (1995) achieved targeted disruption of the Smpd1 gene in transgenic mice. Homozygous mice accumulated sphingomyelin extensively in the reticuloendothelial system of liver, spleen, bone marrow, and lung, as well as in the brain. Most strikingly, the ganglionic cell layer of Purkinje cells of the cerebellum degenerated completely, leading to severe impairment of neuromotor coordination. The picture resembled that of the neurovisceral form of Niemann-Pick disease (type A). Horinouchi et al. (1995) obtained similar results in Asm knockout mice.
Garcia-Barros et al. (2003) investigated the hypothesis that tumor response to radiation is determined not only by tumor cell type but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant 'acid sphingomyelinase' (asmase)-deficient or Bax (600040)-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wildtype microvasculature. Thus, Garcia-Barros et al. (2003) concluded that endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wildtype mice, they were resistant to single-dose radiation up to 20 Gy. Garcia-Barros et al. (2003) concluded that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.
Mari et al. (2004) demonstrated that levels of methionine adenosyltransferase-1-alpha mRNA as well as MAT I/III protein (see MAT1A, 250850) decreased in cultured rat hepatocytes by in situ generation of ceramide from exogenous human placenta SMPD1. Hepatocytes lacking the SMPD1 gene were insensitive to TNF-alpha, but were responsive to exogenous SMPD1-induced downregulation of MAT1A. In an in vivo model of lethal hepatitis by TNF-alpha, depletion of S-adenosyl-L-methionine (SAM) preceded activation of caspases 8 and 3, massive liver damage, and death of wildtype mice. In contrast, minimal hepatic SAM depletion, caspase activation, and liver damage were seen in Smpd1 -/- mice. Moreover, therapeutic treatment with SAM abrogated caspase activation and liver injury, thus rescuing Smpd1 +/+ mice from TNF-alpha-induced lethality. Mari et al. (2004) concluded that these findings indicated a new role for SMPD1 in TNF-alpha-induced liver failure through downregulation of MAT1A and suggested that maintenance of SAM might be useful in the treatment of acute and chronic liver disease.
In mouse hepatocytes, Lang et al. (2007) demonstrated that Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, which are events prevented by inhibition of Asm. In LEC rats, a model of Wilson disease (277900), deficiency in or pharmacologic inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected the rats from acute hepatocyte death, liver failure, and early death. Patients with Wilson disease showed elevated plasma levels of ASM, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Lang et al. (2007) concluded that Cu(2+) triggers hepatocyte apoptosis through activation of ASM and release of ceramide, suggesting a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.
Levran et al. (1990, 1991) used polymerase chain reaction (PCR) to amplify the coding region from the acid sphingomyelinase gene from an Ashkenazi Jewish patient with Niemann-Pick disease type A (257200). Sequence analysis revealed a single G-to-T change at nucleotide 1487 (in a CpG dinucleotide), predicting an arginine-to-leucine amino acid substitution in residue 496. The mutation was found in 5 of 20 (25%) Ashkenazi Jewish type A patients and in 3 of 36 (8.3%) SMPD1 alleles from non-Jewish type A homozygotes. The mutation was found in only 1 of 90 SMPD1 alleles from normal persons of Ashkenazi Jewish descent. The arg496-to-leu mutation was found in one of the mutant alleles in 2 Ashkenazi Jewish patients with type B Niemann-Pick disease and in none of the alleles of 15 non-Jewish type B homozygotes. The R496L mutation was found in about 32% of Ashkenazi Jewish type A Niemann-Pick disease alleles studied. In contrast, only about 5% of the alleles from non-Jewish type A patients had this mutation (Levran et al., 1991).
In an Ashkenazi Jewish patient with Niemann-Pick disease type B (607616), Levran et al. (1991) identified a 3-base deletion at nucleotides 1821-1823 which predicted the removal of an arginine residue from position 608 of the acid sphingomyelinase polypeptide. The other cDNA clone from this patient had the R496L mutation previously identified in type A Niemann-Pick disease patients (607608.0001). The delta-R608 mutation was not found in 15 unrelated non-Jewish type B patients, with the notable exception of 1 mildly affected patient of Arab descent who was homoallelic for the delta-R608 mutation. These results indicated that the delta-R608 mutation predicts the type B Niemann-Pick disease phenotype, even in the presence of the R496L type A allele, thereby providing the first genotype/phenotype correlation for this lysosomal storage disease. Although only 2 patients had been studied, it appeared that the delta-R608 mutation was a frequent cause of type B Niemann-Pick disease in Ashkenazi Jews. The terms homoallelic and heteroallelic (for genetic compound) seem to have been used particularly by Desnick and his colleagues, e.g., Levran et al. (1991); they are useful terms for the situations repeatedly encountered as more and more intragenic lesions are identified in mendelian disorders.
Niemann-Pick disease type B has a high frequency in the Maghreb region of North Africa, which includes Morocco, Algeria, and Tunisia. In a study of 15 unrelated, non-Jewish North African type B patients, Vanier et al. (1993) found that 12 were homozygous and 2 compound heterozygous for the arg608-to-del mutation. They found the mutation in only 1 of 16 alleles from type B patients from other geographic areas (France, U.K., Italy, Czechoslovakia). A varying severity of the clinical and enzymatic expression was observed in homozygotes for this mutation.
The R608 deletion mutation was found in a 55-year-old Belgian woman of Caucasian origin who had had progressive Parkinson disease for the previous 4 years and presented for acute onset of severe back pain, pain in the rib cage due to multiple vertebral fractures, as well as dyspnea due to interstitial lung disease (Volders et al., 2002). The patient was short statured as a child and the parents were first cousins. The vertebral fractures were thought to be due to increased physical activity after treatment of Parkinson disease, a genetic predisposition, and worsening disease due to interfering medication. She was treated with cholesterol-lowering drugs such as statins to decrease sphingomyelin synthesis, avoidance of drugs that inhibit sphingomyelinase, and bisphosphonates. No new fractures occurred, but the interstitial lung disease progressed.
Fernandez-Burriel et al. (2003) reported that the R608 deletion was the most prevalent among patients in Gran Canaria Island in patients with Niemann-Pick disease. They estimated the prevalence of the disease as 0.8-1:100,000 in their community; all patients carried the arg608-to-del mutation. Because of the heterogeneity of the clinical phenotype and the high prevalence of the arg608-to-del mutation in their community, they suggested that the mutation be routinely tested for in adults with hepatosplenomegaly of unknown origin before trying more invasive tests such as liver or bone marrow biopsy.
Rodriguez-Pascau et al. (2009) identified the R608del mutation in 38% of alleles from 21 patients of Spanish origin with Niemann-Pick disease. All patients with the R608del mutation had type B disease. In vitro functional expression studies in COS-7 cells showed that the mutant protein had 21.46% residual activity. Haplotype analysis suggested a founder effect.
By sequence analysis of mRNA and genomic DNA of fibroblasts from a patient with Niemann-Pick disease type A (257200), Ferlinz et al. (1991) showed a G-to-A transition at nucleotide 1729 resulting in substitution of serine for glycine at position 577.
In a 19-year-old Japanese female with type B Niemann-Pick disease (607616) manifested by moderate hepatosplenomegaly and mild pulmonary involvement and without neuronopathic manifestations, Takahashi et al. (1992) found a ser436-to-arg mutation in homoallelic state. Her affected sister had the same mutation and both parents were heterozygous.
In a type A Niemann-Pick disease (257200) patient of Asian Indian ancestry, Takahashi et al. (1992) found homoallelism for a T-to-A transversion in exon 2, predicting a premature stop at codon leucine-261.
Takahashi et al. (1992) found that a type A Niemann-Pick disease (257200) patient of European ancestry was heteroallelic for a 2-base (TT) deletion in exon 2, which caused a frameshift mutation at SMPD1 codon 178, leading to a premature stop at codon 190. The mutation on the other chromosome was a G-to-A transition in exon 3 which caused a methionine-to-isoleucine substitution at codon 382 (M382I).
See 607608.0006. Transient expression of the L261X (607608.0005), L178FS (607608.0006), and M382I mutations in COS-1 cells demonstrated that these lesions did not produce catalytically active enzyme, consistent with the severe neuronopathic type A Niemann-Pick disease (257200) phenotype.
Takahashi et al. (1992) found that a type B Niemann-Pick disease (607616) patient of European descent was heteroallelic for 2 missense mutations: a G-to-A transition in exon 2 which predicted a glycine-to-arginine substitution at codon 242 (G242R), and an A-to-G transition in exon 3 which resulted in an asparagine-to-serine substitution at codon 383 (N383S).
See 607608.0008. Takahashi et al. (1992) found that the G242R allele (607608.0008) produced enzyme activity in COS-1 cells at levels about 40% of that expressed by the normal allele, thereby explaining the mild Niemann-Pick disease type B (607616) phenotype of the patient and the high residual activity (approximately 15% of normal) in cultured lymphoblasts. In contrast, the other allele, N383S, did not produce catalytically active enzyme.
Levran et al. (1992) reported a T-to-C transition at nucleotide 905, predicting a leucine-to-proline substitution at SMPD1 codon 302 in 8 of 34 (23.5%) Ashkenazi type A Niemann-Pick disease (257200) alleles studied. In contrast, it was not found in any of the SMPD1 alleles from non-Jewish type A patients or in alleles from type B patients or in 100 SMPD1 alleles from normal Ashkenazi Jewish persons. The authenticity of the frequent R496L (607608.0001) and L302P mutations was confirmed by separately introducing each nucleotide change into the full-length SMPD1 cDNA by site-directed mutagenesis and transient expression in COS-1 cells. Neither mutation expressed SMPD1 catalytic activity.
Levran et al. (1993) described a new mutation that causes type A Niemann-Pick disease (257200) in Ashkenazi Jewish patients. Deletion of a single cytosine in codon 330 of the SMPD1 cDNA (which normally encodes a proline residue) caused a frameshift that led to the formation of a premature stop (TGA) at codon 382. The mutation occurred in 4 of 52 SMPD1 alleles analyzed from unrelated Ashkenazi Jewish type A patients or obligate heterozygotes. In contrast, the mutation was not found in non-Jewish type A patients or in any Jewish or non-Jewish type B patients. Three mutations, R496L (607608.0001), L302P (607608.0010), and this mutation, account for about 65% of the mutant SMPD1 alleles in Ashkenazi Jewish type A Niemann-Pick disease patients. The single base deletion causing the pro330FS mutation was in a region of the gene where 9 of the 10 residues were cytosines.
In a kindred with its roots in a small village of Serbia, Sperl et al. (1994) described 6 members affected by an atypical intermediate form of Niemann-Pick disease (see 257200) with a visceral course and additional retinal changes, namely macular halos, indicative of neuronal storage. A very low degradation rate of sphingomyelin was demonstrated in skin fibroblasts. Ferlinz et al. (1995) demonstrated a novel mutation, a T-to-G transversion at nucleotide 1171 (nucleotides counted from the A of the first putative initiation codon, ATG), resulting in a substitution of glycine (GGG) for the normal tryptophan (TGG) at amino acid position 391. Northern analysis did not show significant aberration in quantity and size of the mRNA compared with normals. The family contained an example of pseudodominance resulting from the marriage of a homozygote with a heterozygote. Three of 4 children were homozygotes. Ferlinz et al. (1995) concluded that instability and rapid breakdown of the mature mutant enzyme protein due to the mutation was the primary mechanism for deficiency of sphingomyelinase activity in these patients, rather than direct inactivation of catalytic activity.
In 28 Saudi Arabian cases of type B Niemann-Pick disease (607616), Simonaro et al. (2002) found that his421-to-tyr (H421Y) was the most frequent mutation, accounting for 71.4% of mutant alleles. The mutation occurs within the putative active-site region of the enzyme and at a histidine residue that might be involved in zinc binding. The mutation was associated with an early onset and a more severe form of type B Niemann-Pick disease.
Lee et al. (2003) studied a family in which a brother and sister were compound heterozygotes for the R608 deletion (607608.0002) and an arg441-to-ter (R441X) mutation in the SMPD1 gene. The proband, a 47-year-old man, had been admitted to a pediatric hospital at the age of 3 years for failure to thrive and hepatosplenomegaly. Patchy pulmonary infiltrates were found without obvious infectious cause, and splenectomy was performed. The diagnosis of type B Niemann-Pick disease (607616) was made on the basis of lipid-laden histiocytes on histopathology. Subsequent physical and neurologic development were normal and he worked as a mechanic. His sister, who was 2 years younger, was also diagnosed with type B Niemann-Pick disease on the basis of splenectomy. Her physical and intellectual development proceeded normally. At age 41 years, she was found to have severe coronary artery disease and underwent coronary artery bypass. Lee et al. (2003) concluded that compound heterozygosity for the 2 mutations was associated with low HDL cholesterol and premature coronary artery disease.
In 2 unrelated patients with Niemann-Pick disease type B (607616), Pavlu and Elleder (1997) identified a homozygous 874C-A transversion in exon 2 of the SMPD1 gene, resulting in a gln292-to-lys (Q292K) substitution. Both patients had progressive visceral manifestations, and 1 developed neurologic symptoms.
Pavlu-Pereira et al. (2005) found that the Q292K mutation was associated with an intermediate form of Niemann-Pick disease characterized by a protracted neurovisceral phenotype (see 257200).
In a Spanish patient with Niemann-Pick disease type A (257200), Rodriguez-Pascau et al. (2009) identified a homozygous 1445C-A transversion in exon 5 of the SMPD1 gene, resulting in an ala482-to-glu (A482E) substitution. Two additional patients were compound heterozygous for this mutation and another pathogenic mutation. In vitro functional expression studies in COS-7 cells showed that the mutant protein had less than 5% residual activity.
In a Spanish patient with Niemann-Pick disease type A (257200), Rodriguez-Pascau et al. (2009) identified a homozygous 1400A-C transversion in exon 5 of the SMPD1 gene, resulting in a tyr467-to-ser (Y467S) substitution. In vitro functional expression studies in COS-7 cells showed that the mutant protein had less than 5% residual activity.
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