Table 2.
Overview of Mutations in the Human LEPR
| First Author and Year of Publication | Overview: LEPR Mutations |
||||||
|---|---|---|---|---|---|---|---|
| Number of Cases (n) | Case ID | Patient Nationality | Mutation in the Coding DNA (c.) | Mutation in the Mature Protein (p.) | Affected Domain | Provided Functional Analysis | |
| Clement et al. 1998 [6] | 3 | Clem_1.1, Clem_1.2, Clem_1.3 | Algerian | c.2597 + 1G>A | n.a. | FNIII | PCR and sequencing |
| Farooqi et al. 2007 [30] | 2 | Far_2.2, Far_2.1 | Turkish | n.a. | 11-bp del in codon 70 | NTD | In silico |
| Farooqi et al. 2007 [30] | 3 | Far_4.3, Far_4.2, Far_4.1 | Southern European | n.a. | p.W31* | NTD | n.a. |
| Farooqi et al. 2007 [30] | 1 | Far_3 | Iranian | n.a. | 66-bp del in codon 514 | CRHII | In silico |
| Farooqi et al. 2007 [30] | 1 | Far_5 | Turkish | c.1226C>A | p.A409E | IGD | In vitro |
| Farooqi et al. 2007 [30] | 1 | Far_6 | Norwegian | n.a. | p.W664R | FNIII | In vitro |
| Farooqi et al. 2007; [30] Ulm | 2 | Far_7; Ulm_3 | White (United Kingdom); German | c.2051A>C | p.H684P | FNIII | In vitro |
| Le Beyec et al. [35] 2013 | 1 | Bey_1 | French | c.1871dupA | p.N624Kfs*21 | CRHII + FNIII | In silico |
| Kakar et al. 2013 [40] | 5 | Kak_1.1.1, Kak_1.1.2, Kak_1.2, Kak_1.3. Kak_1.4 | Pakistani | c.1603 + 5G>C | p.R468Sfs*33 | CRHII | In silico |
| Gill et al. 2013 [42] | 2 | Gil_2.1, Gil_2.2 | Sudanese | c.479delA | p.H160Lfs*10 | CRHI | In silico |
| Gill et al. 2013 [42] | 1 | Gil_1 | Guinean | c.556delT | p.C186Afs*28 | CRHI | In silico |
| Saeed et al. 2014 and 2015 [34, 38] | 4 | Sae_2, Sae2_3, Sae2_4, Sae2_5 | Pakistani | c.2396-1G>T | n.a. | FNIII | In silico |
| Saeed et al. 2014 and 2015 [34, 38] | 2 | Sae_1, Sae2_6 | Pakistani | c.1675G>A | p.W558* | CRHII | In silico Ilumina, Sanger |
| Huvenne et al. 2015 [32] | 1 | Huv_2 | French | c.1810T>G | p.C604G | CRHII | In silico |
| Huvenne et al. 2015 [32] | 1 | Huv_3 | Portuguese | c.2357T>C | p.L786P | FNIII | In silico |
| Huvenne et al. 2015 [32] | 1 | Huv_4 | Turkish | c.2491G>A | p.H800_N831del | FNIII | In silico |
| Huvenne et al. 2015 [32] | 5 | Huv_5, Huv_6, Huv_7, Huv_8, Huv_9 | French (Reunion Island) | Del exon 6–8 | p.P166Cfs*7 | CRHI | In silico, PCR |
| Ulm | 1 | Ulm_1 | Turkish | Del exon 4–20 | n.a. | CRHI-NTD | n.a. |
| Ulm | 1 | Ulm_4 | German | Comp. het. c.2227 T>C and c.2598-3_2607delTAGAATGAAAAAG | Comp. het. p.S743P and p.Q865_K870 | FNIII + CRHII | In silico |
| Ulm | 1 | Ulm_5 | Turkish | p.N154Kfs*3 | c.461dupA | CRHI | In silico |
| Ulm | 1 | Ulm_6 | German | Comp. het. c.1874G>A and c.2051A>C | Comp. het. p.W625* and p.H684P | FNIII + CRHII | In vitro (p.H684P; see Farooqi et al. 2007 [30]) |
| Farooqi et al. 2007 [30] | 3 | Far_1.3, Far_1.2, Far_1.1 | Bangladeshi | n.a. | 4-bp del in codon 22 | NTD | In silico |
| Maezen et al. 2011 [37] | 2 | Maz_1, Maz_2 | Egyptian | c.946C>A | p.P316T | CRHI | In silico |
| Andiran et al. 2011 [31]; Ulm | 2 | And_1, Ulm_2 | Turkish | c.946C>A and c. n.a. | p.P316T and p.W646C (both homozygous) | CRHI + FNIII | In silico |
| Huvenne et al. 2015 [32] | 1 | Huv_10 | French (Reunion Island) | Comp. het. c.1604–1G>A and del exon 6–8 | Comp. het. p. n.a and p.P166Cfs*7 | CRHII + CRHI | In silico |
| Hannema et al. 2016 [33] | 1 | Han_2 | Dutch | c.1604–8A>G | K536Sfs*34 and p.V535Dfs*3a | CRHII | In silico |
| Vauthier et al. 2012 [39] | 1 | Vau_1 | French | Del of DNAJC6 and parts of LEPR | n.a. | NTD + CRII | PCR, MPLC |
| Huvenne et al. 2015 [32] | 2 | Huv_11.1, Huv_11.2 | French | Comp. het. c.1264T>C and c.2131dup | Comp. het. p.Y422H and p.T711N fs*18 | IGD + FNIII | In silico |
| Saeed et al. 2015 [34] | 2 | Sae2_2.1, Sae2_2.2 | Pakistani | c.1810T>A | p.C604S | CRHII | In silico |
| Saeed et al. 2015 [34] | 1 | Sae2_1 | Pakistani | Mutation not in transcript | n.a. | — | In silico |
| Hannema et al. 2016 [33] | 1 | Han_1 | Dutch | Comp. het. c.1753–1dupG and c.2168C>T | Comp. het. p.M585Dfs*2 and p.S723F | CRHII | In silico Ilumina, Sanger |
| Farooqi et al. 2007 [30] | 1 | Far_8 | White (United Kingdom) | Comp. het. c. n.a. and c.1835G>A | Comp. het. 1 bp del in codon 15 and p.R612H | NTD + CRHII | In vitro (p.R612H) |
Included are number of cases, case ID and nationality, location of the mutation in the LEPR protein, affected domain, and provided information about functional analysis. Estimation of the functional relevance of the respective mutation was made based on predefined criteria. Criteria for functional relevance were (1) highly suspicious BMI, (2) hypogonadotropic hypogonadism, (3) consanguineous parents, (4) highly suspicious variant, and (5) conclusive functional analysis. Conclusions on functional relevance are based on the number of fulfilled criteria: “High” indicates high evidence for complete loss of LEPR function (three to five criteria fulfilled); “Probably” indicates that the mutation is probably damaging (two to three criteria); “Low” indicates low evidence for functional relevance, with in vitro analyses necessary to exclude residual function of LEPR (two or fewer criteria).
Abbreviations: c., cDNA position in the gene; comp. het., compound heterozygous; del, deletion; fs, frameshift; HH, hypogonadotropic hypogonadism; MPLC, medium pressure liquid chromatography, n.a., no information available; p., amino acid position in the protein; Rf, residual function; *, premature stop codon.
Published as corresponding to p.K597Sfs*34 and p.V596Dfs*3 in the original paper. Based on the experimentally validated changes in the RNA, we assume the correct mutations to be p.K536Sfs*34 and p.V535Dfs*3.