Table 1.
Non-synonymous CUZD1 variants in European subjects with non-alcoholic CP and controls
| Exon | Nucleotide change | Amino acid change | rs number | SIFT | CADD | PROVEAN | PredictSNP | Secretion (% of WT) | CP (n=1,163) n (%) | Controls (n=2,018) n (%) | p-value | OR | 95% CI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | c.46T>C | p.S16P | rs1003444066 | 0.33 | 8.6 | Neutral | Neutral | 79 | 0 | 1 (0.05) | 1.0 | ||
| 1 | c.71C>A | p.A24E | rs565610081 | 0.15 | 11.1 | Neutral | Neutral | 128 | 1 (0.09) | 0 | 0.37 | ||
| 2 | c.220T>G | p.F74V | - | 0 | 23.8 | Deleterious | Deleterious | 83 | 1 (0.09) | 0 | 0.37 | ||
| 3 | c.283G>A | p.G95R | rs764182845 | 0.01 | 21.5 | Deleterious | Deleterious | 49 | 0 | 1 (0.05) | 1.0 | ||
| 3 | c.335A>G | p.Y112C | rs148941738 | 0.14 | 11.9 | Neutral | Neutral | 78 | 0 | 1 (0.05) | 1.0 | ||
| 3 | c.421T>C | p.F141L | - | 0.13 | 23.7 | Neutral | Neutral | 77 | 0 | 1 (0.05) | 1.0 | ||
| 3 | c.442A>C | p.N148H | - | 0.1 | 7.4 | Neutral | Neutral | 97 | 0 | 1 (0.05) | 1.0 | ||
| 4 | c.506A>G | p.N169S | rs141623717 | 0.17 | 22.7 | Neutral | Neutral | 111 | 2 (0.17) | 3 (0.15) | 1.0 | ||
| 4 | c.508T>C | p.Y170H | - | 0 | 26.1 | Deleterious | Deleterious | 112 | 0 | 1 (0.05) | 1.0 | ||
| 5 | c.608T>G | p.I203R | rs148411775 | 0.02 | 16.3 | Neutral | Neutral | 89 | 2 (0.17) & | 1 (0.05) | 0.28 | ||
| 5 | c.610G>T | p.D204Y | rs747068473 | 0 | 23.7 | Deleterious | Deleterious | 91 | 0 | 1 (0.05) | 1.0 | ||
| 5 | c.620G>A | p.C207Y | - | 0 | 23.8 | Deleterious | Deleterious | 18 | 1 (0.09) | 1 (0.05) | 1.0 | ||
| 5 | c.681A>T | p.Q227H | rs200891112 | 0.04 | 23.4 | Neutral | Neutral | 110 | 1 (0.09) § | 0 | 0.37 | ||
| 5 | c.686G>C | p.C229S | - | 0 | 25.8 | Deleterious | Deleterious | 41 | 1 (0.09) | 0 | 0.37 | ||
| 5 | c.692G>A | p.R231H | rs144483251 | 0.51 | 17.3 | Neutral | Neutral | 94 | 3 (0.26)$ | 10 (0.5) | 0.4 | ||
| 5 | c.764A>G | p.Y255C | - | 0 | 27.1 | Deleterious | Deleterious | 62 | 1 (0.09) | 0 | 0.37 | ||
| 5 | c.782C>T | p.S261F | - | 0.44 | 23.8 | Deleterious | Deleterious | 98 | 0 | 1 (0.05) | 1.0 | ||
| 6 | c.854T>C | p.I285T | rs36212072 | 0.21 | 22.8 | Neutral | Neutral | 88 | 13 (1.11)% | 27 (1.35) | 0.63 | ||
| 6 | c.958G>A | p.V320I | rs201994934 | 1 | 11.0 | Neutral | Neutral | 95 | 2 (0.17) | 1 (0.05) | 0.28 | ||
| 6 | c.965T>C | p.L322P | rs762907320 | 0 | 25.4 | Deleterious | Deleterious | 31 | 1 (0.09) | 2 (0.1) | 1.0 | ||
| 6 | c.989A>G | p.K330R | rs759790848 | 0.06 | 24.9 | Neutral | Neutral | 95 | 0 | 1 (0.05) | 1.0 | ||
| 7 | c.1064G>A | p.R355H | rs188322992 | 0.01 | 23.7 | Deleterious | Deleterious | 61 | 2 (0.17) | 0 | 0.13 | ||
| 7 | c.1172G>A | p.G391D | - | 0.05 | 23.9 | Deleterious | Deleterious | 27 | 1 (0.09) | 0 | 0.37 | ||
| 8 | c.1385G>A | p.C462Y | rs1242843548 | 0 | 29.1 | Deleterious | Deleterious | 52 * | 3 (0.26) | 0 | 0.049 | ∞ | NaN−∞ |
| 8 | c.1423G>C | p.G475R | rs1035904361 | 0.56 | 14.4 | Neutral | Neutral | 105 | 1 (0.09) | 0 | 0.37 | ||
| 8 | c.1442insC | p.Q481Pfs * | rs770045215 | - | - | - | - | 1 | 1 (0.09) | 0 | 0.37 | ||
| 8 | c.1531C>T | p.R511C | rs373802557 | 0 | 32.0 | Deleterious | Deleterious | 50 | 2 (0.17) | 0 | 0.13 | ||
| 9 | c.1661A>G | p.H554R | rs61730786 | 0.48 | 0.1 | Neutral | Neutral | 123 | 1 (0.05) | 0 | 0.37 | ||
| 9 | c.1754C>T | p.A585V | rs948370801 | 0.48 | 7.6 | Neutral | Neutral | 103 | 0 | 2 (0.1) | 0.54 | ||
| 9 | c.1772A>C | p.H591P | rs1238211350 | 0.01 | 20.7 | Neutral | Deleterious | 72 | 0 | 1 (0.05) | 1.0 | ||
| Subjects carrying predicted deleterious CUZD1 variants (%) | |||||||||||||
| SIFT | 17 (1.5) | 8 (0.4) | 0.002 | 3.7 | 1.6–8.7 | ||||||||
| CADD score ≥25 | 9 (0.8) | 3 (0.2) | 0.012 | 5.2 | 1.4–19.4 | ||||||||
| PROVEAN | 14 (1.2) | 7 (0.4) | 0.006 | 3.5 | 1.4–8.7 | ||||||||
| PredictSNP | 14 (1.2) | 8 (0.4) | 0.013 | 3.1 | 1.3–7.3 | ||||||||
| All (SIFT-CADD25-PROVEAN-PredictSNP) | 9 (0.8) | 3 (0.2) | 0.012 | 5.2 | 1.4–19.4 | ||||||||
| All (SIFT-CADD20-PROVEAN-PredictSNP) | 14 (1.2) | 6 (0.3) | 0.004 | 4.1 | 1.6–10.7 | ||||||||
| Secretion <50% | 5 (0.4) | 4 (0.2) | 0.29 | 2.4 | 0.6–8.9 | ||||||||
CUZD1 variants with a deleterious prediction or less than 50% secretion are in bold. P-values were determined by two-tailed Fisher’s exact test.
Percent secretion are means of two densitometric measurements from two independent Western blots.
Reduced secretion of p.C462Y is probably due to weaker binding of antibody HPA068479 and could not be confirmed with a second antibody (sc-514578).
One patient was homozygous for SPINK1 p.N34S
This patient was heterozygous for CFTR p.S1235R
One patient was heterozygous for SPINK1 p.N34S and one patient heterozygous for TRPV6 p.L299Q
One patient each was heterozygous for SPINK1 c.194+2T>C, one for CFTR p.F508del and one for TRPV6 p.L299Q and the CEL-HYB1 hybrid allele