Identification and metabolic profiling of patients with lysosomal acid lipase deficiency.
BACKGROUND
Lysosomal acid lipase (LAL), encoded by the LIPA gene, catalyzes the intracellular hydrolysis of cholesteryl esters and triglycerides in hepatocytes and macrophages. LIPA defects cause accumulation of these lipids in lysosomes. LAL deficiency (LAL D) presents and progresses as a continuum with dyslipidemia, hepatomegaly, and liver fibrosis.


OBJECTIVE
To improve the understanding of the genetic basis of LAL D, an underappreciated cause of dyslipidemia and cirrhosis, we studied DNA samples from patients with various phenotypes of dyslipidemia.


METHODS
Participants (N = 1357) were identified by lipid profiles and screened for the common disease causing LIPA exon 8 skipping splice-site mutation (c.894G>A; p.Ser275_Gln298del; rs116928232).


RESULTS
Six patients were heterozygous for this variant. Complete LIPA sequencing revealed a patient, subsequently confirmed to have LAL D, with a heterozygous frameshift mutation involving deletion of exon 4 (p.Gly77Valfs*17 c.230-106_c.428+541del). A family study revealed a sister with the same genotype and phenotype. Genetic, clinical, and lipoprotein profiles of these sisters plus 6 additional family members are reported. Profiles of 2 other LAL D patients monitored for 2 decades are presented. Cholesterol homeostasis was studied to investigate rates of cholesterol synthesis and absorption in 4 LAL D patients. High-density lipoprotein (HDL) subspecies were also analyzed.


CONCLUSIONS
We used this LIPA sequencing strategy (detection of the relatively common exon 8 variant followed by complete gene sequencing to identify additional mutations) as a means to further elucidate the genetic basis of LAL D among individuals with a suggestive clinical phenotype.
Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Physiological Nursing, University of California, San Francisco, CA, USA. Electronic address: clive.pullinger@ucsf.edu.
Clive R
CR
Pullinger
Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA.
Eveline Oestreicher
EO
Stock
Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Irina
I
Movsesyan
Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA.
Mary J
MJ
Malloy
Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA.
Philip H
PH
Frost
Synageva BioPharma Corp, Lexington, MA, USA.
Radhika
R
Tripuraneni
Synageva BioPharma Corp, Lexington, MA, USA.
Anthony G
AG
Quinn
Boston Heart Diagnostics, Framingham, MA, USA.
Brian Y
BY
Ishida
Boston Heart Diagnostics, Framingham, MA, USA.
Ernst J
EJ
Schaefer
Boston Heart Diagnostics, Framingham, MA, USA.
Bela F
BF
Asztalos
Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics.
John P
JP
Kane
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D009154:Mutation; D002787:Sterol Esterase / Q000235:genetics; D015223:Wolman Disease / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D008075:Lipoproteins, HDL; D002787:Sterol Esterase
Cholesterol; Cholesteryl ester storage disease; DNA mutational analysis; LIPA; Lysosomal acid lipase; Lysosomal acid lipase deficiency; Wolman disease