Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema
Abstract
:1. Introduction
2. Materials and Methods
2.1. Clinical Evaluation
2.2. Genetic Analysis
2.3. In-Silico Analysis
3. Results
3.1. Clinical and Genetic Evaluation
3.2. In Silico Analysis, Template Selection and Building
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
NGS | Next-Generation Sequencing |
NRP1/2 | Neuropilin 1/2 |
LECs | Lymphatic endothelial cells |
References
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Characteristics | NRP1 | NRP2 |
---|---|---|
Localization | 10p11.22 | 2q33.3 |
Gene function | Protein coding | Protein coding |
Expression in lymphatic system | Predominantly lymphatic valves | Small lymphatic vessels and capillaries |
Lethality in mouse model | Embryo death at E8.5 (Nrp1−/−/Nrp2−/−) Embryo death at E10-E10.5 (Nrp1+/−/Nrp2−/−; Nrp1−/−/Nrp2+/−) | |
Lymphatic phenotype in mouse model | Nrp1−/− malformation of valve precursor LECs [18] | Nrp2−/− reduction or loss of small lymphatic vessels and capillaries [19] Nrp2+/− and Vegfr3+/− abnormal lymphatic development and reduced lymphatic vessel branching [13] |
NRP1 | MERGLPLLCAVLALVLAPAGAFRNDKCGDTIKIESPGYLTSPGYPHSYHPSEKCEWLIQAPDPYQRIMINFNPHFDLEDRDCKYDYVEVFDGENENGHFRGKFCGKIAPPPVVSSGPFLFIKFVSDYETHGAGFSIRYEIFKRGPECSQNYTTPSGVIKSPGFPEKYPNSLECTYIVFVPKMSEIILEFESFDLEPDSNPPGGMFCRYDRLEIWDGFPDVGPHIGRYCGQKTPGRIRSSSGILSMVFYTDSAIAKEGFSANYSVLQSSVSEDFKCMEALGMESGEIHSDQITASSQYSTNWSAERSRLNYPENGWTPGEDSYREWIQVDLGLLRFVTAVGTQGAISKETKKKYYVKTYKIDVSSNGEDWITIKEGNKPVLFQGNTNPTDVVVAVFPKPLITRFVRIKPATWETGISMRFEVYGCKITDYPCSGMLGMVSGLISDSQITSSNQGDRNWMPENIRLVTSRSGWALPPAPHSYINEWLQIDLGEEKIVRGIIIQGGKHRENKVFMRKFKIGYSNNGSDWKMIMDDSKRKAKSFEGNNNYDTPELRTFPALSTRFIRIYPERATHGGLGLRMELLGCEVEAPTAGPTTPNGNLVDECDDDQANCHSGTGDDFQLTGGTTVLATEKPTVIDSTIQSEFPTYGFNCEFGWGSHKTFCHWEHDNHVQLKWSVLTSKTGPIQDHTGDGNFIYSQADENQKGKVARLVSPVVYSQNSAHCMTFWYHMSGSHVGTLRVKLRYQKPEEYDQLVWMAIGHQGDHWKEGRVLLHKSLKLYQVIFEGEIGKGNLGGIAVDDISINNHISQEDCAKPADLDKKNPEIKIDETGSTPGYEGEGEGDKNISRKPGNVLKTLDPILITIIAMSALGVLLGAVCGVVLYCACWHNGMSERNLSALENYNFELVDGVKLKKDKLNTQSTYSEA |
NRP2 | MDMFPLTWVFLALYFSRHQVRGQPDPPCGGRLNSKDAGYITSPGYPQDYPSHQNCEWIVYAPEPNQKIVLNFNPHFEIEKHDCKYDFIEIRDGDSESADLLGKHCGNIAPPTIISSGSMLYIKFTSDYARQGAGFSLRYEIFKTGSEDCSKNFTSPNGTIESPGFPEKYPHNLDCTFTILAKPKMEIILQFLIFDLEHDPLQVGEGDCKYDWLDIWDGIPHVGPLIGKYCGTKTPSELRSSTGILSLTFHTDMAVAKDGFSARYYLVHQEPLENFQCNVPLGMESGRIANEQISASSTYSDGRWTPQQSRLHGDDNGWTPNLDSNKEYLQVDLRFLTMLTAIATQGAISRETQNGYYVKSYKLEVSTNGEDWMVYRHGKNHKVFQANNDATEVVLNKLHAPLLTRFVRIRPQTWHSGIALRLELFGCRVTDAPCSNMLGMLSGLIADSQISASSTQEYLWSPSAARLVSSRSGWFPRIPQAQPGEEWLQVDLGTPKTVKGVIIQGARGGDSITAVEARAFVRKFKVSYSLNGKDWEYIQDPRTQQPKLFEGNMHYDTPDIRRFDPIPAQYVRVYPERWSPAGIGMRLEVLGCDWTDSKPTVETLGPTVKSEETTTPYPTEEEATECGENCSFEDDKDLQLPSGFNCNFDFLEEPCGWMYDHAKWLRTTWASSSSPNDRTFPDDRNFLRLQSDSQREGQYARLISPPVHLPRSPVCMEFQYQATGGRGVALQVVREASQESKLLWVIREDQGGEWKHGRIILPSYDMEYQIVFEGVIGKGRSGEIAIDDIRISTDVPLENCMEPISAFAGENFKVDIPEIHEREGYEDEIDDEYEVDWSNSSSATSGSGAPSTDKEKSWLYTLDPILITIIAMSSLGVLLGATCAGLLLYCTCSYSGLSSRSCTTLENYNFELYDGLKHKVKMNHQKCCSEA |
Gene | Family | Pedigree | Sex | Age | Clinical Features | Age of Onset | Familial Case | Variant Nomenclature (NRP1: NM_003873.6; NP_001019799.1; NRP2: NM_003872.2; NP_003863.2) | dbSNP id | ACMG Classification | Frequency in GnomAD |
---|---|---|---|---|---|---|---|---|---|---|---|
NRP1 | 1 | Proband | M | 68 | lymphedema of the lower limbs | Juvenile | NO | c.2557A > C; p.Ile853Leu | rs760388137 | Likely benign | 0.0001178 |
NRP1 | 2 | Proband | F | 54 | edema of left foot and ankle | 27 | YES | c.1655G > A; p.Arg552Gln | rs757990959 | VUS | 0.00004873 |
NRP1 | 2 | Daughter | F | 21 | lymphedema of left lower limb | 10 | YES | c.1655G > A; p.Arg552Gln | |||
NRP2 | 1 | Proband | F | 18 | edema of left hand | Congenital | NO | c.580T > G; p.Phe194Val | rs755679361 | VUS | 0.000008122 |
NRP2 | 1 | Mother | F | 44 | Healthy | / | NO | - | |||
NRP2 | 1 | Father | M | 46 | Apparently healthy but with subclinical symptoms | / | NO | c.580T > G; p.Phe194Val | |||
NRP2 | 2 | Proband | M | 9 | edema of left foot, ankle and heel since vaccination | 3 months | NO | c.1748T > C; p.Ile583Thr | rs746130411 | VUS | 0.000004068 |
NRP2 | 3 | Proband | F | 45 | edema of right foot | 32 | YES | c.838C > T; p.Pro280Ser | rs79750907 | Likely benign | 0.001783 |
NRP2 | 3 | Son | M | 15 | edema of left foot | 9 | YES | c.838C > T; p.Pro280Ser | |||
NRP2 | 4 | Proband | F | 50 | swelling of lower limbs | 42 | NO | c.1000C > T; p.Arg334Cys | rs114144673 | Likely benign | 0.001525 |
Template | Seq Identity | Oligo State | QSQE | Found by | Method | Resolution | Seq Similarity | Coverage | Description | |
---|---|---|---|---|---|---|---|---|---|---|
NRP1 | 4gz9.1.A | 91.50 | monomer | - | BLAST | X-ray | 2.70Å | 0.60 | 0.61 | Neuropilin-1 |
4gz9.1.A | 91.50 | monomer | - | HHBlits | X-ray | 2.70Å | 0.60 | 0.61 | Neuropilin-1 | |
2qql.1.A | 51.95 | Homodimer | 0.37 | HHBlits | X-ray | 3.10Å | 0.46 | 0.61 | Neuropilin-2 | |
2qql.1.A | 53.14 | Homodimer | 0.35 | BLAST | X-ray | 3.10Å | 0.47 | 0.60 | Neuropilin-2 | |
2qqk.1.A | 51.95 | Monomer | - | HHBlits | X-ray | 2.75Å | 0.48 | 0.61 | Neuropilin-2 | |
2qqk.1.A | 53.14 | Monomer | - | BLAST | X-ray | 2.75Å | 0.47 | 0.60 | Neuropilin-2 | |
2qqm.1.A | 99.78 | monomer | - | BLAST | X-ray | 2.00Å | 0.62 | 0.48 | Neuropilin-1 | |
2qqm.1.A | 99.78 | monomer | - | HHBlits | X-ray | 2.00Å | 0.62 | 0.48 | Neuropilin-1 | |
2qqo.1.A | 51.36 | monomer | - | HHBlits | X-ray | 2.30Å | 0.46 | 0.48 | Neuropilin-2 | |
2qqo.1.A | 52.51 | monomer | - | BLAST | X-ray | 2.30Å | 0.46 | 0.47 | Neuropilin-2 | |
NRP2 | 2qql.1.A | 100.00 | Homo-monomer | 0.51 | BLAST | X-ray | 3.10 Å | 0.62 | 0.62 | Neuropilin-2 |
2qqk.1.A | 100.00 | monomer | - | BLAST | X-ray | 2.75Å | 0.62 | 0.62 | Neuropilin-2 | |
2qql.1.A | 100.00 | Homodimer | 0.51 | HHBlits | X-ray | 3.10Å | 0.62 | 0.61 | Neuropilin-2 | |
2qqk.1.A | 100.00 | monomer | - | HHBlits | X-ray | 2.75Å | 0.62 | 0.61 | Neuropilin-2 | |
2qqo.1.A | 100.00 | Monomer | - | HHBlits | X-ray | 2.30Å | 0.62 | 0.48 | Neuropilin-2 | |
2qqm.1.A | 51.81 | Monomer | - | HHBlits | X-ray | 2.00Å | 0.46 | 0.47 | Neuropilin-1 | |
2qqm.1.A | 53.05 | monomer | - | BLAST | X-ray | 2.00Å | 0.46 | 0.48 | Neuropilin-1 | |
2qqj.1.A | 100.00 | monomer | - | BLAST | X-ray | 1.95Å | 0.62 | 0.34 | Neuropilin-2 | |
2qqj.1.A | 100.00 | monomer | - | HHBlits | X-ray | 1.95Å | 0.62 | 0.34 | Neuropilin-2 | |
2qqi.1.A | 51.77 | monomer | - | BLAST | X-ray | 1.80Å | 0.46 | 0.33 | Neuropilin-1 |
Variant | Amino Acid | Molecular Interactions | Bond Length in Angstroms | Bond Type | |
---|---|---|---|---|---|
NRP1 FAM2 | Arg552Gln | Arg552 | Arg552: N–Glu550: O | 3.66 | H-bond |
Arg552: N–Glu550: O | 4.39 | H-bond | |||
Val498: N–Arg552: O | 2.95 | H-bond | |||
Arg552: N–Val498: O | 2.92 | H-bond | |||
Arg552: N–Glu541: O | 2.81 | H-bond | |||
Arg552: N–Gly542: O | 2.76 | H-bond | |||
Gly497: C–Arg552: O | 3.14 | H-bond | |||
Gln552 | Val498: N–Gln552: O | 2.95 | H-bond | ||
Gln552: N–Val498: O | 2.92 | H-bond | |||
Gly497: C–Gln552: O | 3.14 | H-bond |
Variant | Amino Acid | Molecular Interactions | Bond Length in Angstroms | Bond Type | |
---|---|---|---|---|---|
NRP2 FAM 1 | Phe194Val | Phe194 | Thr232: C–Phe194: O | 3.66 | H-bond |
Phe194: A–Phe196 | 4.76 | H-bond | |||
Phe1941: A–Phe213 | 5.44 | Pi interaction | |||
Phe194: A–Pro235 | 4.60 | Pi interaction | |||
Val194 | Thr232: C–Val194: O | 3.66 | H-bond | ||
Val194: A–Pro235 | 4.64 | Hydrophobic interaction | |||
NRP2 FAM 3 | Pro280Ser | Pro280 | Phe425–Pro280 | 4.99 | Pi interaction |
Ser280 | No bonds | - | - | ||
NRP2 FAM 4 | Arg334Cys | Arg334 | Arg334: N–Glu291: O | 2.67 | H-bond |
Arg334: N–Asp332: O | 4.59 | H-bond | |||
Arg334: N–Asp332: O | 2.82 | H-bond | |||
Arg334: N–Tyr229: O | 2.87 | H-bond | |||
Asp332: C–Arg334: N | 3.32 | H-bond | |||
Arg334–Ile226 | 5.10 | Hydrophobic interaction | |||
Cys334 | Cys334: N - Asp332: O | 2.82 | H-bond | ||
Asp332: C–A:Cys334:N | 3.32 | H-bond | |||
A:Cys334–A:Ile226 | 5.18 | Hydrophobic interaction | |||
NRP2 FAM 2 | Ile583Thr | Ile583 | Ile583: N–Pro479: O | 2.80 | H-bond |
Phe475: C–Ile583: O | 3.80 | H-bond | |||
Pro476: C–Ile583: O | 3.41 | H-bond | |||
Ile583: C–Trp578 | 3.89 | Pi interactions | |||
Pro476: A–Ile583 | 4.23 | Pi interactions | |||
Trp578: A–Ile583 | 4.91 | Pi interactions | |||
Thr583 | Thr583: N–Pro479: O | 2.80 | H-bond | ||
Phe475: C–Thr583: O | 3.80 | H-bond | |||
Pro476: C–Thr583: O | 3.41 | H-bond | |||
Thr583: O–Trp578 | 4.09 | Pi interactions |
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Michelini, S.; Amato, B.; Ricci, M.; Kenanoglu, S.; Veselenyiova, D.; Kurti, D.; Baglivo, M.; Manara, E.; Dundar, M.; Krajcovic, J.; et al. Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema. Genes 2020, 11, 1361. https://doi.org/10.3390/genes11111361
Michelini S, Amato B, Ricci M, Kenanoglu S, Veselenyiova D, Kurti D, Baglivo M, Manara E, Dundar M, Krajcovic J, et al. Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema. Genes. 2020; 11(11):1361. https://doi.org/10.3390/genes11111361
Chicago/Turabian StyleMichelini, Sandro, Bruno Amato, Maurizio Ricci, Sercan Kenanoglu, Dominika Veselenyiova, Danjela Kurti, Mirko Baglivo, Elena Manara, Munis Dundar, Juraj Krajcovic, and et al. 2020. "Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema" Genes 11, no. 11: 1361. https://doi.org/10.3390/genes11111361