Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families
Abstract
:1. Introduction
2. Results
2.1. Clinical Characteristics and Biochemical Analysis of the Probands and Their Relatives
2.2. Genetic Analysis
2.3. The Founder p.(Arg490Trp) Variant
2.4. Impact of the p.(Arg490Trp) Mutation on Plasma PCSK9 Levels
3. Discussion
4. Materials and Methods
4.1. Study Participants
4.2. Laboratory and Biochemical Tests
4.3. DNA Analysis and Variant Detection
4.4. In Silico Analysis of the Variant
4.5. Haplotype Analysis
4.6. PCSK9 Measurements
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Subject | Age | Gender | TC | HDL-C | TG | LDL-C § | LDL-C # | ApoB (g/L) | Plasma PCSK9 Levels (ng/mL) | Fatty Liver | Diabetes | Neurological Problem | HBL | APOE Isoforms | p.Leu21dup in PCSK9 | p.(Arg490Trp) in APOB |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
(mmol/L) | ||||||||||||||||
Family 1 | ||||||||||||||||
I.1 | 61 | M | 1.89 | 1.03 | 0.54 | 0.64 | 0.17 | 53.70 | Yes | No | Parkinson’s disease | Yes | ε3/ε3 | No | Yes | |
I.2 | 54 | F | 5.49 | 0.77 | 1.29 | 4.40 | 1.14 | 67.74 | No | No | No | ε2/ε3 | No | No | ||
II.1 ¥ | 28 | F | 2.12 | 1.42 | 0.27 | 0.44 | 0.10 | 29.36 ¶ | Yes | No | Yes | ε2/ε3 | No | Yes | ||
II.2 * | 25 | F | 2.48 | 1.24 | 2.26 | 0.44 | 0.11 | 34.41 | No | No | Yes | ε3/ε3 | No | Yes | ||
II.3 | 21 | M | 3.47 | 1.03 | 0.68 | 2.22 | 0.57 | 57.02 | No | No | No | ε2/ε3 | No | No | ||
II.4 | 16 | F | 2.25 | 1.50 | 0.42 | 0.44 | 0.10 | 34.01 | No | No | Yes | ε2/ε3 | No | Yes | ||
Family 2 | ||||||||||||||||
I.1 | 93 | M | 4.19 | 0.98 | 2.21 | 2.21 | N/A | N/A | Yes | No | N/A | N/A | N/A | |||
I.2 | 73 | F | 1.84 | 0.93 | 0.47 | 0.70 | N/A | N/A | Yes | Yes | N/A | N/A | N/A | |||
II.1 | 53 | M | 4.16 | 1.73 | 0.71 | 2.11 | N/A | N/A | Yes | No | N/A | N/A | N/A | |||
II.2 | 52 | F | 2.59 | 1.14 | 1.69 | 0.68 | 0.45 | 68.35 | No | Yes | Yes | ε3/ε3 | Yes | Yes | ||
II.3 ¥ | 47 | F | 2.72 | 0.88 | 0.75 | 1.50 | 0.40 | 34.16 | No | No | Yes | ε3/ε3 | No | Yes | ||
Family 3 | ||||||||||||||||
I.1 | 90 | M | No | Yes | Multiple System Atrophy | Yes | ε3/ε3 | No | Yes | |||||||
II.1 ¥ | 60 | F | 2.69 | 1.08 | 0.93 | 1.08 | 0.41 | 68.98 | No | Yes | Yes | ε3/ε3 | No | Yes | ||
Proband 4 | 49 | M | 1.60 | 0.88 | 0.59 | 0.45 | N/A | Yes | Yes | Yes | ε3/ε3 | No | Yes | |||
Proband 5 | 63 | F | 2.38 | 0.96 | 1.41 | 0.78 | N/A | Yes | Yes | Neuropathies | Yes | ε3/ε3 | Yes | Yes | ||
Proband 6 | 33 | F | 3.96 | 2.43 | 0.34 | 1.38 | N/A | N/A | No | Yes | ε3/ε3 | No | No | |||
Proband 7 | 23 | F | 3.21 | 1.47 | 0.67 | 1.44 | 0.66 | 69.39 | N/A | No | Yes | ε3/ε3 | No | No | ||
Mean ± SD p.(Arg490Trp)carriers(n = 9) | 2.30 ± 0.38 | 1.13 ± 0.22 | 0.83 ± 0.50 | 0.72 ± 0.36 | 0.25 ± 0.16 | 48.94 ± 17.05 |
Haplotype of the APOB-p.(Arg490Trp) Carriers | |||||||||
---|---|---|---|---|---|---|---|---|---|
Haplotype Marker | Reference SNP [29,30] | Nucleotide Change (NM_000384.3) | Amino Acid Change (Original/Present Nomenclature NP_000375.3) | Prevalence in Non-Finnish European (GnomAD) | Proband (II.1) and Affected Members of Family 1 | Proband (II.3) and Member (II.2) of Family 2 | Proband (II.1) and Member (I.1) of Family 3 | Proband 4 | Proband 5 |
HincII | Intron 4 | c | c | c | c | c | |||
PvuII | Intron 4 | g | g | g | g | g | |||
Heterozygous for p.(Arg490Trp) | rs771541567 | c.1468C>T | p.(Arg463Trp)/p.(Arg490Trp) | 0.000017 | T | T | T | T | T |
AluI | rs679899 | c.1853C>T | p.(Ala591Val)/p.(Ala618Val) | 0.47 | C | C | C | C | C |
XbaI | rs693 | c.7545C>T | p.(Thr2488=)/p.(Thr2515=) | 0.499 | T | T | T | T | T |
MspI | rs1801701 | c.10913G>A | p.(Arg3611Gln)/p.(Arg3638Gln) | 0.091 | G | G | G | G | G |
EcoRI | rs1042031 | c.12541G>A | p.(Glu4154Lys)/p.(Glu4181Lys) | 0.182 | G | G | G | G | G |
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Ayoub, C.; Azar, Y.; Abou-Khalil, Y.; Ghaleb, Y.; Elbitar, S.; Halaby, G.; Jambart, S.; Gannagé-Yared, M.-H.; Yaghi, C.; Saade Riachy, C.; et al. Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families. Metabolites 2021, 11, 564. https://doi.org/10.3390/metabo11090564
Ayoub C, Azar Y, Abou-Khalil Y, Ghaleb Y, Elbitar S, Halaby G, Jambart S, Gannagé-Yared M-H, Yaghi C, Saade Riachy C, et al. Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families. Metabolites. 2021; 11(9):564. https://doi.org/10.3390/metabo11090564
Chicago/Turabian StyleAyoub, Carine, Yara Azar, Yara Abou-Khalil, Youmna Ghaleb, Sandy Elbitar, Georges Halaby, Selim Jambart, Marie-Hélène Gannagé-Yared, Cesar Yaghi, Carole Saade Riachy, and et al. 2021. "Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families" Metabolites 11, no. 9: 564. https://doi.org/10.3390/metabo11090564
APA StyleAyoub, C., Azar, Y., Abou-Khalil, Y., Ghaleb, Y., Elbitar, S., Halaby, G., Jambart, S., Gannagé-Yared, M. -H., Yaghi, C., Saade Riachy, C., El Khoury, R., Rabès, J. -P., Varret, M., Boileau, C., El Khoury, P., & Abifadel, M. (2021). Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families. Metabolites, 11(9), 564. https://doi.org/10.3390/metabo11090564