Alternative titles; symbols
HGNC Approved Gene Symbol: LIPA
SNOMEDCT: 57218003, 82500001; ICD10CM: E75.5;
Cytogenetic location: 10q23.31 Genomic coordinates (GRCh38): 10:89,213,572-89,251,775 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.31 | Cholesteryl ester storage disease | 278000 | Autosomal recessive | 3 |
| Wolman disease | 620151 | Autosomal recessive | 3 |
Anderson and Sando (1991) reported that the amino acid sequence of lysosomal acid lipase (LAL; cholesteryl ester hydrolase; EC 3.1.1.13) as deduced from the 2.6-kb cDNA nucleotide sequence is 58% identical to that of human gastric lipase (LIPF; 601980), which is involved in the preduodenal breakdown of ingested triglycerides.
Anderson et al. (1994) isolated and sequenced the gene for LIPA.
The distinct kinetic and physical properties of lipases A and B (LIPB; 247980) were defined by Warner et al. (1980). They stated that the natural substrate for LIPB was not known, and that it was not clear that LIPB is a lysosomal hydrolase. LIPA may serve an important role in cellular metabolism by releasing cholesterol. The liberated cholesterol suppresses further cholesterol synthesis and stimulates esterification of cholesterol within the cell.
Aslanidis et al. (1994) summarized the exon structure of the LIPA gene, which consists of 10 exons, together with the sizes of genomic EcoRI and SacI fragments hybridizing to each exon. The DNA sequence of the putative promoter region was presented.
Anderson et al. (1994) found that the LIPA gene is spread over 36 kb of genomic DNA. The 5-prime flanking region is GC-rich and has characteristics of a 'housekeeping' gene promoter.
Koch et al. (1979, 1981) assigned lysosomal acid lipase A to chromosome 10 by human-Chinese hamster somatic cell hybrids. Judging from the close concordance with soluble glutamate oxaloacetate transaminase (GOT1; 138180), these loci were thought to be close together on the long arm of 10. Lipase A is encoded by chromosome 19 in mouse (Koch et al., 1981). GOT1 is also on chromosome 10q in man and 19 in mouse.
By fluorescence in situ hybridization, Anderson et al. (1993) mapped the LIPA locus to 10q23.2-q.23.3. It was clearly distinct from the locus for pancreatic lipase (246600) at 10q26.1.
Cholesteryl ester storage disease (CESD; 278000) and Wolman disease (WOLD; 620151) are autosomal recessive allelic disorders associated with reduced activity and genetic defects of lysosomal acid lipase. Aslanidis et al. (1996) provided evidence that the strikingly more severe course of Wolman disease is caused by genetic defects of LAL that leave no residual enzyme activity. In a CESD patient, a G-to-A transition at position -1 of the exon 8 splice donor site (613497.0002) resulted in skipping of exon 8 in 97% of the mRNA originating from this allele, while 3% was spliced correctly, resulting in full-length LAL enzyme. Two sibs with Wolman disease were homozygous for a splice site mutation involving the same donor site but permitting no correct splicing or subsequent synthesis of functional enzyme (613497.0004).
Pagani et al. (1996) described the molecular basis of CESD in 3 patients. They identified mutations by sequence analysis of LAL cDNA and genomic DNA. The role of the mutations as the direct cause of the disease was confirmed by measuring the LAL enzymatic activity of extracts from cells transfected with LAL mutants. The 3 CESD patients were found to be compound heterozygotes. Pagani et al. (1996) identified 3 different missense mutations, 2 splicing defects, and a null allele.
In an Azerbaijani girl, born to consanguineous parents, with CESD, Bychkov et al. (2019) identified homozygosity for a synonymous mutation in the LIPS gene (613497.0008) that was predicted to result in abnormal splicing. Analysis of patient mRNA showed a deletion of 63-bp in exon 6 of the LIPA transcript, corresponding to activation of a cryptic splice site. The parents were found to be heterozygous for the mutation.
Wolman Disease
In a proband with Wolman disease (WOLD; 620151) from a nonconsanguineous family, Anderson et al. (1994) detected a T-to-C transition at nucleotide 639 of the LIPA gene that resulted in a nonconservative missense mutation, leu179 to pro (L179P). This mutation was found in compound heterozygosity with a single-base insertion resulting in a null allele (613497.0004). The proband had had 2 older sibs with Wolman disease. Anderson et al. (1994) noted that the L179P mutation is located 26 amino acids from the predicted active site of lysosomal acid lipase and was expected to disrupt the alpha-helical structure in a highly conserved region of the protein.
Cholesteryl Ester Storage Disease
Maslen and Illingworth (1993) and Maslen et al. (1995) found the L179P mutation in 2 sibs with cholesteryl ester storage disease (CESD; 278000). In these sibs the L179P mutation, inherited from the mother, was found in compound heterozygosity with a splice site mutation that resulted in skipping of exon 8 of lysosomal acid lipase (613497.0002). Maslen et al. (1995) compared the phenotypes of other patients carrying the L179P or the splice site mutation described by them and concluded that the L179P mutant allele apparently does not make a substantial contribution to cholesteryl ester hydrolase activity.
In a 12-year-old patient with cholesteryl ester storage disease (CESD; 278000) from a nonconsanguineous Polish-German family, Klima et al. (1993) detected a 72-bp in-frame deletion resulting in the loss of amino acid codons 254 through 277. Analysis of genomic DNA revealed that the 72 bp represented an exon, indicating that the deletion in the mRNA was caused by defective splicing. Sequence analysis of the patient's genomic DNA revealed a G-to-A substitution in the last nucleotide of the 72-bp exon on 1 allele. No normal-sized mRNA was detectable in the propositus even though he was not homozygous for the splice site mutation. Klima et al. (1993) concluded that the patient was compound heterozygous for the splice site mutation and a null allele. The patient showed LIPA activity in cultured skin fibroblasts approximately 9% of normal. Hepatosplenomegaly had been present since age 5 years.
Aslanidis et al. (1996) restudied the patient of Klima et al. (1993) and defined the splice site mutation as a G-to-A mutation at position -1 of the splice donor site following exon 8, resulting in incorrect splicing and the removal of the 72-bp exon 8 of the LIPA gene. They determined that the other allele of the patient carried a premature termination mutation (613497.0003) as well as the L179P mutation (613497.0001); the LIPA mRNA was rendered unstable by the premature stop codon. Aslanidis et al. (1996) demonstrated that the splice site mutation allowed the production of approximately 3 to 4% of correctly spliced mRNA relative to wildtype. Aslanidis et al. (1996) also identified a mutation at the same splice donor site, and also resulting in deletion of exon 8, in 2 sibs with Wolman disease; that mutation, at the +1 position, allowed no correct splicing, and patient fibroblasts were devoid of enzymatic activity. See 613497.0005.
In 2 sibs with CESD, Maslen and Illingworth (1993) and Maslen et al. (1995) identified compound heterozygosity for this splice site mutation in the LIPA gene, inherited from their father, and the L179P mutation (613497.0001). The affected children were a sister and brother who presented with idiopathic hepatomegaly at ages 6 and 8 years, respectively. Subsequent analyses indicated that they also had hypercholesterolemia and a severe reduction in cholesteryl ester hydrolase activity in cultured fibroblasts.
Muntoni et al. (1995) observed homozygosity for the splice site mutation (Klima et al., 1993) in a Spanish kindred with cholesterol ester storage disease. Exon 8 of the LIPA gene was deleted.
Aslanidis et al. (1996) determined that the patient of Klima et al. (1993) with cholesteryl ester storage disease (CESD; 278000) was compound heterozygous for a G-to-T transversion at nucleotide 836 in exon 7 of the LIPA gene, resulting in substitution of gly245 with a termination codon (G245X), and a splice site mutation resulting in skipping of exon 8 (613497.0002). The allele carrying the G245X mutation also carried the L179P mutation (613497.0001). Aslanidis et al. (1996) concluded that although the L179P mutation is believed to abolish the enzymatic activity of the lysosomal acid lipase, it is the G245X mutation, through its production of an unstable mRNA, that was responsible for the low level of transcript (approximately 6% of wildtype) derived from the paternal allele.
Wolman Disease
In a proband with Wolman disease (WOLD; 620151), Anderson et al. (1994) found compound heterozygosity for insertion of a T nucleotide after nucleotide 634 in exon 6 of the LIPA gene, and a substitution of proline at leucine-179 (613497.0001). The 634T insertion occurred at the end of a run of 6 Ts and led to premature termination 12 amino acids downstream.
Cholesteryl Ester Storage Disease
Anderson et al. (1994) also found this mutation in a proband and parent from 1 of 11 unrelated families with cholesteryl ester storage disease (CESD; 278000) examined.
In 2 sibs with Wolman disease (WOLD; 620151) from a consanguineous family, Aslanidis et al. (1996) detected homozygosity for a G-to-A mutation at position +1 of the splice donor site following exon 8 of the LIPA gene. Both children died within the first year of life. The parents, who were heterozygous for the mutation, had reduced enzymatic activity, while no enzymatic activity was detectable in fibroblasts from the affected children. Although the same donor splice site is involved in the mutation reported in CESD (934G-A, 613497.0002), the nucleotide at position +1 was changed in the Wolman disease mutation whereas the nucleotide at position -1 was changed in the CESD mutation. Both mutations result in deletion of the same 24 amino acids (exon 8), but the effects are dramatically different: the -1 mutation allowed some correct splicing (3% of total LIPA RNA), but the +1 splice site mutation, which affects one of the invariable nucleotides of the splice consensus sequences, permits no correct splicing. Aslanidis et al. (1996) suggested that the residual activity in CESD patients compared to Wolman patients may result either from a partially active enzyme with the internal deletion of 24 amino acids (skipping of exon 8) or from the production of low amounts of the full size of the protein due to inefficient exon exclusion from the mutated allele.
In a Japanese patient with Wolman disease (WOLD; 620151), Fujiyama et al. (1996) identified a tyr22-to-ter (Y22X) mutation of the LIPA gene. The female patient had an umbilical cord herniation at birth. At about 30 days after birth, she showed abdominal distention with hepatosplenomegaly and frequent episodes of diarrhea and vomiting. Abdominal computed tomography revealed massive hepatosplenomegaly and enlargement of the adrenal glands with calcification. Anemia and hepatic failure progressed rapidly and she died at age 114 days. The parents were first cousins. An older sister had died with similar symptoms 80 days after birth.
In an infant, born of unrelated parents, with Wolman disease (WOLD; 620151), Lee et al. (2011) identified compound heterozygous mutations in the LIPA gene. One allele carried a heterozygous 1-bp deletion (482delA) in exon 5, resulting in a frameshift and premature termination at residue 179. The mutation, which was inherited from the unaffected father, was not found in 200 controls chromosomes. The other allele, inherited from the unaffected mother, carried an intragenic deletion including intron 3 and part of exon 4; both the patient and mother had only 1 copy of exon 4. The patient presented at age 6 weeks with abdominal distention and failure to thrive. He had hepatosplenomegaly and calcified adrenals; LIPA activity was undetectable. He died of multiorgan failure within the following month.
In an Azerbaijani girl, born to consanguineous parents, with cholesteryl ester storage disease (CESD; 278000), Bychkov et al. (2019) identified homozygosity for a synonymous c.600G-A transition in exon 6 of the LIPA gene that was predicted to result in abnormal splicing. The mutation was identified by direct gene sequencing, and both parents were confirmed to be carriers. The mutation was not present in the ExAC and gnomAD databases or in 100 control chromosomes. Analysis of patient mRNA showed a deletion of 63-bp (c.539_601del) in exon 6 of the LIPA transcript, corresponding to activation of a cryptic splice site, and analysis of her parent's mRNA showed both the expected wildtype transcript and a transcript with the 63-bp deletion in exon 6. Molecular modeling predicted that the deletion was located close to the active site, affecting highly conserved amino acids, and likely had an impact on protein activity. Lysosomal acid lipase activity was low in patient leukocytes and in a dried blood spot.
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Anderson, R. A., Rao, N., Byrum, R. S., Rothschild, C. B., Bowden, D. W., Hayworth, R., Pettenati, M. In situ localization of the genetic locus encoding the lysosomal acid lipase/cholesteryl esterase (LIPA) deficient in Wolman disease to chromosome 10q23.2-q23.3. Genomics 15: 245-247, 1993. [PubMed: 8432549] [Full Text: https://doi.org/10.1006/geno.1993.1052]
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Bychkov, I. O., Kamenets, E. A., Filatova, A. Y., Skoblov, M. Y., Mikhaylova, S. V., Strokova, T. V., Gundobina, O. S., Zakharova, E. Y. The novel synonymous variant in LIPA gene affects splicing and causes lysosomal acid lipase deficiency. Molec. Genet. Metab. 127: 212-215, 2019. [PubMed: 31230978] [Full Text: https://doi.org/10.1016/j.ymgme.2019.06.005]
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Koch, G., Lalley, P. A., McAvoy, M., Shows, T. B. Assignment of LIPA, associated with human acid lipase deficiency to human chromosome 10 and comparative assignment to mouse chromosome 19. Somat. Cell Genet. 7: 345-358, 1981. [PubMed: 7292252] [Full Text: https://doi.org/10.1007/BF01538859]
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Muntoni, S., Wiebusch, H., Funke, H., Ros, E., Seedorf, U., Assmann, G. Homozygosity for a splice junction mutation in exon 8 of the gene encoding lysosomal acid lipase in a Spanish kindred with cholesterol ester storage disease (CESD). Hum. Genet. 95: 491-494, 1995. [PubMed: 7759067] [Full Text: https://doi.org/10.1007/BF00223858]
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