Best matches for Lysosomal Acidic lipase deficiency:
Infant case of lysosomal acid lipase deficiency: Wolman's disease.
Sadhukhan M et al. BMJ Case Rep.
(2014)
Lysosomal lipase deficiency: molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease.
Fasano T et al. Mol Genet Metab.
(2012)
1.
Duta-Mare
M, Sachdev V, Leopold C, Kolb D, Vujic N, Korbelius M, Hofer DC, Xia W,
Huber K, Auer M, Gottschalk B, Magnes C, Graier WF, Prokesch A, Radovic
B, Bogner-Strauss JG, Kratky D.
Biochim Biophys Acta. 2018 Apr;1863(4):467-478. doi: 10.1016/j.bbalip.2018.01.011. Epub 2018 Jan 31.
Biochim Biophys Acta. 2018 Apr;1863(4):467-478. doi: 10.1016/j.bbalip.2018.01.011. Epub 2018 Jan 31.
Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis.
Duta-Mare M1, Sachdev V1, Leopold C1, Kolb D2, Vujic N1, Korbelius M1, Hofer DC3, Xia W3, Huber K3, Auer M1, Gottschalk B1, Magnes C4, Graier WF5, Prokesch A1, Radovic B5, Bogner-Strauss JG6, Kratky D7.
Abstract
Abstract
Lysosomal acid lipase
(LAL) is the only known enzyme, which hydrolyzes cholesteryl esters and
triacylglycerols in lysosomes of multiple cells and tissues. Here, we
explored the role of LAL in brown adipose tissue (BAT). LAL-deficient
(Lal-/-) mice exhibit markedly reduced UCP1 expression in BAT, modified
BAT morphology with accumulation of lysosomes, and mitochondrial
dysfunction, consequently leading to regular hypothermic events in mice
kept at room temperature. Cold exposure resulted in reduced lipid uptake
into BAT, thereby aggravating dyslipidemia and causing life threatening
hypothermia in Lal-/- mice. Linking LAL as a potential regulator of
lipoprotein lipase activity, we found Angptl4 mRNA expression upregulated in BAT. Our data demonstrate that LAL is critical for shuttling fatty acids derived from circulating lipoproteins to BAT during cold exposure. We conclude that inhibited lysosomal lipid hydrolysis in BAT leads to impaired thermogenesis in Lal-/- mice.KEYWORDS:
Brown adipose tissue; Dyslipidemia; LAL deficiency; Lysosome; Thermogenesis; UCP1
Free PMC Article
2.
Tuohetahuntila M, Molenaar MR, Spee B, Brouwers JF, Wubbolts R, Houweling M, Yan C, Du H, VanderVen BC, Vaandrager AB, Helms JB.
J Biol Chem. 2017 Jul 28;292(30):12436-12448. doi: 10.1074/jbc.M117.778472. Epub 2017 Jun 14.
Activation of hepatic stellate cells (HSCs) is a critical step in the
development of liver fibrosis. During activation, HSCs lose their lipid
droplets (LDs) containing triacylglycerols (TAGs), cholesteryl esters,
and retinyl esters (REs). We previously provided evidence for the
presence of two distinct LD pools, a preexisting and a dynamic LD pool.
Here we investigate the mechanisms of neutral lipid metabolism in the
preexisting LD pool. To investigate the involvement of lysosomal degradation of neutral lipids, we studied the effect of lalistat, a specific lysosomal acid lipase (LAL/Lipa) inhibitor on LD degradation in HSCs during activation in vitro
The LAL inhibitor increased the levels of TAG, cholesteryl ester, and
RE in both rat and mouse HSCs. Lalistat was less potent in inhibiting
the degradation of newly synthesized TAG species as compared with a more
general lipase inhibitor orlistat. Lalistat also induced the presence of RE-containing LDs in an acidic
compartment. However, targeted deletion of the Lipa gene in mice
decreased the liver levels of RE, most likely as the result of a gradual
disappearance of HSCs in livers of Lipa-/- mice. Lalistat
partially inhibited the induction of activation marker α-smooth muscle
actin (α-SMA) in rat and mouse HSCs. Our data suggest that LAL/Lipa is
involved in the degradation of a specific preexisting pool of LDs and
that inhibition of this pathway attenuates HSC activation.Free PMC Article
3.
Chuang JC, Lopez AM, Turley SD.
Biochem Pharmacol. 2017 Jul 1;135:116-125. doi: 10.1016/j.bcp.2017.03.010. Epub 2017 Mar 18.
- PMID:
- 28322747
4.
Xu X, Yuan X, Li N, Dewey WL, Li PL, Zhang F.
J Cell Mol Med. 2016 Jun;20(6):1001-13. doi: 10.1111/jcmm.12788. Epub 2016 Jan 28.
The disruption in transportation of oxLDL-derived cholesterol and the
subsequent lipid accumulation in macrophages are the hallmark events in
atherogenesis. Our recent studies demonstrated that lysosomal
Ca(2+) messenger of nicotinic acid adenine dinucleotide phosphate
(NAADP), an enzymatic product of CD38 ADP-ribosylcyclase (CD38),
promoted lipid endocytic trafficking in human fibroblast cells. The
current studies are designed to examine the functional role of
CD38/NAADP pathway in the regulation of lysosomal
cholesterol efflux in atherosclerosis. Oil red O staining showed that
oxLDL concentration-dependently increased lipid buildup in bone
marrow-derived macrophages from both wild type and CD38(-/-) , but to a
significant higher extent with CD38 gene deletion. Bodipy 493/503
fluorescence staining found that the deposited lipid in macrophages was
mainly enclosed in lysosomal
organelles and largely enhanced with the blockade of CD38/NAADP
pathway. Filipin staining and direct measurement of lysosome fraction
further revealed that the free cholesterol constituted a major portion
of the total cholesterol segregated in lysosomes. Moreover, in situ
assay disclosed that both lysosomal lumen acidity and the acid lipase
activity were reduced upon cholesterol buildup in lysosomes. In
CD38(-/-) mice, treatment with Western diet (12 weeks) produced
atherosclerotic damage in coronary artery with striking lysosomal
cholesterol sequestration in macrophages. These data provide the first
experimental evidence that the proper function of CD38/NAADP pathway
plays an essential role in promoting free cholesterol efflux from
lysosomes and that a defection of this signalling leads to lysosomal cholesterol accumulation in macrophages and results in coronary atherosclerosis in CD38(-/-) mice.Free PMC Article
5.
Zhao T, Du H, Blum JS, Yan C.
Oncotarget. 2016 Jan 12;7(2):1529-43. doi: 10.18632/oncotarget.6414.
Lysosomal acid lipase
(LAL) is a key enzyme controlling neutral lipid metabolic signaling in
myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient
(lal-/-) mice directly stimulate cancer cell proliferation. PPARγ ligand
treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and
metastasis in vivo, and tumor cell proliferation and migration in vitro.
In addition, PPARγ ligand treatment impaired lal-/- MDSCs
transendothelial migration, and differentiation from lineage-negative
cells. The corrective effects of PPARγ ligand on lal-/- MDSCs functions
were mediated by regulating the mammalian target of rapamycin (mTOR)
pathway, and subsequently blocking MDSCs ROS overproduction.
Furthermore, in the myeloid-specific dominant-negative PPARγ (dnPPARγ)
overexpression bitransgenic mouse model, tumor growth and metastasis
were enhanced, and MDSCs from these mice stimulated tumor cell
proliferation and migration. MDSCs with dnPPARγ overexpression showed
increased transendothelial migration, overactivation of the mTOR
pathway, and ROS overproduction. These results indicate that PPARγ plays
a critical role in neutral lipid metabolic signaling controlled by LAL,
which provides a mechanistic basis for clinically targeting MDSCs to
reduce the risk of cancer proliferation, growth and metastasis.KEYWORDS:
lipid metabolic signaling; lysosomal acid lipase; myeloid-derived suppressor cells; peroxisome proliferator-activated receptor-γ; tumor growth and metastasis
Free PMC Article
6.
Rajamohan F, Reyes AR, Ruangsiriluk W, Hoth LR, Han S, Caspers N, Tu M, Ward J, Kurumbail RG.Protein Expr Purif. 2015 Jun;110:22-9. doi: 10.1016/j.pep.2014.12.009. Epub 2015 Jan 22.
Lysosomal acid lipase
(LAL) is a serine hydrolase which hydrolyzes cholesteryl ester and
triglycerides delivered to the lysosomes into free cholesterol and free
fatty acids.
Mutations in the LAL gene (LIPA) result in accumulation of triglycerides
and cholesterol esters in various tissues of the body, leading to
pathological conditions such as Wolman's disease (WD) and cholesteryl
ester storage disease (CESD). CESD patients homozygous for His295Tyr
(H295Y) mutation have less than 5% of normal LAL activity. To shed light
on the molecular basis for this loss-of-function phenotype, we have
generated the recombinant H295Y enzyme and studied its biophysical and
biochemical properties. No significant differences were observed in the
expression levels or glycosylation patterns between the mutant and the
wild type LAL. However, the H295Y mutant displayed only residual
enzymatic activity (<5 20="" 5.0="" a="" aggregate.="" amino="" as="" at="" besides="" class="highlight" compared="" exists="" expression="" fibroblasts="" h295y="" has="" high="" his295="" in="" is="" lal="" lower="" majority="" melting="" molecular="" monomer="" mostly="" mutant="" mutation="" of="" other="" ph="" showed="" soluble="" span="" studies="" temperature="" that="" the="" to="" transient="" type.="" type="" vast="" wd="" while="" wild="">acids
Cholesteryl ester storage disease (CESD); LAL-deficiency; Lipid metabolism; Lysosomal acid lipase (LAL); Protein aggregation; Wolman’s disease (WD)
7.
Sadhukhan M, Saha A, Vara R, Bhaduri B.
BMJ Case Rep. 2014 May 15;2014. pii: bcr2013202652. doi: 10.1136/bcr-2013-202652.
Lysosomal acid lipase (LAL) deficiency
is a rare autosomal recessive disorder which causes two distinct
clinical phenotypes: Wolman's disease and cholesterol ester storage
disease. LAL hydrolyses LDL-derived triglycerides and cholesterol esters
to glycerol or cholesterol and free fatty acids. Its deficiency leads to accumulation of intracellular triglycerides and/or cholesterol esters. In early onset LAL deficiency,
clinical manifestations start in the first few weeks of life with
persistent vomiting, failure to thrive, hepatosplenomegaly, liver
dysfunction and hepatic failure. Adrenal calcification is a striking
feature but is present in only about 50% of cases. We report a case of
an infant presenting with vomiting, diarrhoea, hepatosplenomegaly and
poor weight gain that was subsequently diagnosed as Wolman's disease. He
was entered into a clinical trial for LAL replacement therapy. This
case reinforces that early onset LAL deficiency should be considered in a baby presenting with failure to thrive, gastrointestinal symptoms and hepatosplenomegaly.
- PMID:
- 24832708
- PMCID:
- PMC4024536
- DOI:
- 10.1136/bcr-2013-202652
8.
Ding X, Du H, Yoder MC, Yan C.
Am J Pathol. 2014 Feb;184(2):397-408. doi: 10.1016/j.ajpath.2013.10.015. Epub 2013 Nov 26.
Lysosomal acid lipase (LAL) is essential for the hydrolysis of cholesteryl esters and triglycerides to generate cholesterol and free fatty acids
in cellular lysosomes. Ablation of the lal gene (lal(-/-)) systemically
increased expansion of cluster of differentiation molecule 11b (CD11b),
lymphocyte antigen 6G (Ly6G) myeloid-derived suppressor cells (MDSCs)
that caused myeloproliferative neoplasms in mice. Study of lal(-/-) bone
marrow Ly6G(+) MDSCs via transcriptional profiling showed increases in
mammalian target of rapamycin (mTOR) signaling pathway transcripts.
Injection of mTOR pharmacologic inhibitors into lal(-/-) mice
significantly reduced bone marrow myelopoiesis and systemic
CD11b(+)Ly6G(+) cell expansion. Rapamycin treatment of lal(-/-) mice
stimulated a shift from immature CD11b(+)Ly6G(+) cells to CD11b(+)
single-positive cells in marrow and tissues and partially reversed the
increased cell proliferation, decreased apoptosis, increased ATP
synthesis, and increased cell cycling of bone marrow CD11b(+)Ly6G(+)
cells obtained from lal(-/-) mice. Pharmacologic and siRNA suppression
of mTOR, regulatory-associated protein of mTOR, rapamycin-insensitive
companion of mTOR, and Akt1 function corrected CD11b(+)Ly6G(+) cell in
lal(-/-) mice development from Lin(-) progenitor cells and reversed the
immune suppression on T-cell proliferation and function in association
with decreased reactive oxygen species production, and recovery from
impairment of mitochondrial membrane potential compared with control
mutant cells. These results indicate a crucial role of LAL-regulated
mTOR signaling in the production and function of CD11b(+)Ly6G(+) cells.
The mTOR pathway may serve as a novel target to modulate the emergence
of MDSCs in those pathophysiologic states in which these cells play an
immunosuppressive role.Free PMC Article
9.
Thelwall
PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, Thoma C,
Trenell MI, Taylor R, Rutkowski JV, Blamire AM, Quinn AG.
J Hepatol. 2013 Sep;59(3):543-9. doi: 10.1016/j.jhep.2013.04.016. Epub 2013 Apr 25.Abstract BACKGROUND & AIMS:Lysosomal Acid Lipase (LAL) deficiency
is a rare metabolic storage disease, caused by a marked reduction in
activity of LAL, which leads to accumulation of cholesteryl esters (CE)
and triglycerides (TG) in lysosomes in many tissues. We used (1)H
magnetic resonance (MR) spectroscopy to characterize the abnormalities
in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency
rat model. Secondly, we used MR spectroscopy to monitor the effects of
an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant
human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model. METHODS:Human
studies employed cohorts of LAL-deficient patients and NAFLD subjects.
Rat experimental groups comprised ex vivo liver samples of wild type,
NAFLD, LAL-deficient, and LAL-deficient rats receiving 4weeks of
sebelipase alfa treatment. Hepatic (1)H MR spectroscopy was performed
using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic
cholesterol and triglyceride content. RESULTS: CE accumulation was identified in LAL deficiency
in both human and preclinical studies. A significant decrease in
hepatic CE was observed in LAL-deficient rats following treatment with
sebelipase alfa. CONCLUSIONS: We demonstrate an entirely
non-invasive method to identify and quantify the hepatic lipid signature
associated with a rare genetic cause of fatty liver. The approach
provides a more favorable alternative to repeated biopsy sampling for
diagnosis and disease progression / treatment monitoring of patients
with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. KEYWORDS: (1)H
MR spectroscopy; (13)C MR spectroscopy; CE; CESD; Cholesteryl ester
storage disease; ERT; Enzyme replacement therapy; LAL; LAL deficiency; LIPA; Liver fat; Lysosomal acid lipase; NAFLD; Sebelipase alfa; TG; Wolman disease; cholesteryl ester; cholesteryl ester storage disease; enzyme replacement therapy; lysosomal acid lipase; non-alcoholic fatty liver disease; triglyceride
10.
Fasano T, Pisciotta L, Bocchi L, Guardamagna O, Assandro P, Rabacchi C, Zanoni P, Filocamo M, Bertolini S, Calandra S.
Mol Genet Metab. 2012 Mar;105(3):450-6. doi: 10.1016/j.ymgme.2011.12.008. Epub 2011 Dec 17.
Wolman Disease (WD) and cholesteryl ester storage disease (CESD)
represent two distinct phenotypes of the same recessive disorder caused
by the complete or partial deficiency of lysosomal acidic lipase
(LAL), respectively. LAL, encoded by the LIPA gene, hydrolyzes
cholesteryl esters derived from cell internalization of plasma
lipoproteins. WD is a rapidly progressive and lethal disease
characterized by intestinal malabsorption, hepatic and adrenal failure.
CESD is characterized by hepatic fibrosis, hyperlipidemia and
accelerated atherosclerosis. Aim of the study was the identification of
LIPA mutations in three WD and eight CESD patients. The WD patients, all
deceased before the first year of age, were homozygous for two novel
mutations (c.299+1G>A and c.419G>A) or a mutation (c.796G>T)
previously reported as compound heterozygosity in a CESD patient. The
two mutations (c.419G>A and c.796G>T) resulting in truncated
proteins (p.W140* and p.G266*) and the splicing mutation (c.229+1G>A)
were associated with undetectable levels of LIPA mRNA in fibroblasts.
All eight CESD patients carried the common mutation c.894G>A known to
result not only in a major non-functional transcript with the skipping
of exon 8 (p.S275_Q298del), but also in a minor normally spliced
transcript producing 5-10% residual LAL activity. The c.894G>A
mutation was found in homozygosity in four patients and, as compound
heterozygosity, in association with a known (p.H295Y and p.G342R) or a
novel (p.W140*) mutation in four other CESD patients. Segregation
analysis performed in all patients harboring c.895G>A showed its
occurrence on the same haplotype suggesting a common founder ancestor.
The other WD and CESD mutations were associated with different
haplotypes.
11.
Qu P, Yan C, Blum JS, Kapur R, Du H.
J Immunol. 2011 Oct 1;187(7):3854-66. doi: 10.4049/jimmunol.1003358. Epub 2011 Sep 7.
- PMID:
- 21900179
12.
Xie X, Brown MS, Shelton JM, Richardson JA, Goldstein JL, Liang G.
Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15330-5. doi: 10.1073/pnas.1112751108. Epub 2011 Sep 6.
- PMID:
- 21896731
13.
Kaphalia BS, Bhopale KK, Kondraganti S, Wu H, Boor PJ, Ansari GA.
Toxicol Appl Pharmacol. 2010 Aug 1;246(3):154-62. doi: 10.1016/j.taap.2010.05.002. Epub 2010 May 15.
- PMID:
- 20478324
14.
Qu P, Du H, Wilkes DS, Yan C.
Am J Pathol. 2009 Mar;174(3):944-56. doi: 10.2353/ajpath.2009.080562. Epub 2009 Jan 29.
Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids
and cholesterol in lysosomes. In LAL gene-knockout (lal(-/-)) mice,
blockage of cholesteryl ester and triglyceride metabolism led to
abnormal organization of the thymus and spleen, as well as neutral lipid
accumulation in these organs. LAL deficiency
impaired T cell development in the thymus. Peripheral T cells were
reduced dramatically in lal(-/-) mice, due largely to increased
apoptosis and decreased proliferation of lal(-/-) T cells in the thymus
and peripheral compartments. These lal(-/-) T cells lost the ability to
respond to T cell receptor stimulation, including reduced expression of
cell surface receptor CD69, abolishment of T cell proliferation, and
decreased expression of T lymphokines after stimulation by either
anti-CD3 plus anti-CD28 or phorbol-12-myristate-13-acetate and
ionomycin. Differentiation of Th1 and Th2 CD4(+) effector lymphocytes by
T cell receptor stimulation was blocked in lal(-/-) mice. The ratio of
CD4(+)CD25(+)FoxP3(+) Tregs to CD4(+) T cells was increased in lal(-/-)
spleens. Bone marrow chimeras demonstrated retardation of T cell
development and maturation in lal(-/-) mice due to defects in T cell
precursors. Therefore, LAL, its downstream genes, and lipid mediators
all play essential roles in development, homeostasis, and function of T
cells. The altered development and function of lal(-/-) T cells
contributes to disease formation in various organs during LAL deficiency.Free PMC Article
15.
Lu JY, Hofmann SL.
J Lipid Res. 2006 Jul;47(7):1352-7. Epub 2006 Apr 20. Review.
- PMID:
- 16627894
16.
Lian X, Yan C, Qin Y, Knox L, Li T, Du H.
Am J Pathol. 2005 Sep;167(3):813-21.
The functional roles of neutral lipids in the lung are poorly
understood. However, blocking cholesteryl ester and triglyceride
metabolism in lysosomal acid lipase
gene knockout mice (lal-/-) results in severe pathogenic phenotypes in
the lung, including massive neutrophil infiltration, foamy macrophage
accumulation, unwanted cell growth, and emphysema. To elucidate the
mechanism underlining these pathologies, we performed Affymetrix
GeneChip microarray analysis of 1-, 3-, and 6-month-old mice and
identified aberrant gene expression that progressed with age. Among
changed genes, matrix metalloproteinase (MMP)-12, apoptosis inhibitor 6
(Api-6), erythroblast transformation-specific domain (Ets) transcription
factor family member Spi-C, and oncogene MafB were increased 100-, 70-,
40-, and 10-fold, respectively, in lal-/- lungs versus the wild-type
lungs. The pathogenic increases of these molecules occurred primarily in
alveolar type II epithelial cells. Transcriptional activities of the
MMP-12 and Api-6 promoters were stimulated by Spi-C or MafB in
respiratory epithelial cells. Treatment with 9-hydroxyoctadecanoic acids
and ciglitazone significantly rescued lal-/- pulmonary inflammation and
aberrant gene expression. In addition, both compounds as well as
peroxisome proliferator-activated receptor gamma inhibited MMP-12 and
Api-6 promoter activities. These data suggest that
inflammation-triggered cell growth and emphysema during lysosomal acid lipase deficiency are partially caused by peroxisome proliferator-activated receptor-gamma inactivation.Free PMC Article
17.
Lee J, Jiao X, Hejtmancik JF, Kaiser-Kupfer M, Gahl WA, Markello TC, Guo J, Chader GJ.
Invest Ophthalmol Vis Sci. 2001 Jul;42(8):1707-14.
- PMID:
- 11431432
18.
Das AK, Bellizzi JJ 3rd, Tandel S, Biehl E, Clardy J, Hofmann SL.
J Biol Chem. 2000 Aug 4;275(31):23847-51.
Palmitoyl-protein thioesterase-1 (PPT1) is a newly described lysosomal enzyme that hydrolyzes long chain fatty acids from lipid-modified cysteine residues in proteins. Deficiency
in this enzyme results in a severe neurodegenerative storage disorder,
infantile neuronal ceroid lipofuscinosis. Although the primary structure
of PPT1 contains a serine lipase
consensus sequence, the enzyme is insensitive to commonly used
serine-modifying reagents phenylmethylsulfonyl fluoride (PMSF) and
diisopropylfluorophosphate. In the current paper, we show that the
active site serine in PPT1 is modified by a substrate analog of PMSF,
hexadecylsulfonylfluoride (HDSF) in a specific and site-directed manner.
The apparent K(i) of the inhibition was 125 micrometer (in the presence
of 1.5 mm Triton X-100), and the catalytic rate constant for
sulfonylation (k(2)) was 3.3/min, a value similar to previously
described sulfonylation reactions. PPT1 was crystallized after
inactivation with HDSF, and the structure of the inactive form was
determined to 2.4 A resolution. The hexadecylsulfonyl was found to
modify serine 115 and to snake through a narrow hydrophobic channel that
would not accommodate an aromatic sulfonyl fluoride. Therefore, the
geometry of the active site accounts for the reactivity of PPT1 with
HDSF but not PMSF. These observations suggest a structural explanation
as to why certain serine lipases are resistant to modification by
commonly used serine-modifying reagents.Free Article
19.
Redonnet-Vernhet I, Chatelut M, Salvayre R, Levade T.
Hum Mutat. 1998;11(4):335-6.
- PMID:
- 9554751
20.
Ameis D, Brockmann G, Knoblich R, Merkel M, Ostlund RE Jr, Yang JW, Coates PM, Cortner JA, Feinman SV, Greten H.
J Lipid Res. 1995 Feb;36(2):241-50.
Cholesteryl ester storage disease (CESD) results from inherited deficiencies of the lysosomal hydrolase, acid lipase (LAL; E.C. 3.1.1.13). To establish the molecular defects in LAL deficiency,
two unrelated probands with severely reduced LAL activity were
examined. DNA amplification by reverse-transcription polymerase chain
reaction and subsequent sequence analysis of LAL cDNA identified two
mutant alleles. Patient 1, presenting with hepatosplenomegaly, mildly
elevated liver function tests, and hyperlipidemia, was homozygous for a
deletion of nucleotides 823 to 894 of the LAL cDNA. This 72-bp deletion
maintained the reading frame and resulted in a loss of 24 amino acids
from the LAL protein. Analysis of genomic DNA revealed that the 72 bp
corresponded to an exon of the LAL gene. A single G to A point mutation
at the last exon position was observed in the genomic DNA of patient 1,
indicating a splicing defect with consecutive exon skipping underlying
the 72-bp deletion. Patient 2 was a compound heterozygote for the 72-bp
deletion and a dinucleotide deletion at positions 967 and 968. This
deletion resulted in a shifted reading frame carboxyterminal of codon
296, and 43 random amino acids followed the frame shift. A premature stop at codon 339 truncated the mutant LAL protein by 34 amino acids.
Allele-specific hybridization confirmed that patient 1 was homozygous
for the 72-bp deletion mutation, and that patient 2 was a compound
heterozygote for the 72-bp deletion and the 2-bp deletion.Free Article
Inga kommentarer:
Skicka en kommentar