Table 2.
Missense variants and exon deletion of MODY genes in Japanese probands.
| Gene | Protein varianta | Location | Nucleotide changes | Carrier frequency | Clinical information | Possible functional impact | Conservation (protein) | Class | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patients | Controls (n = 100) | Refs. | HGMD professional | Protein level | RNA level | |||||||
| Polyphen-2/SIFT | Splice | ESE/ESS | ||||||||||
| GCK | M41T | Exon 2 | c.122 T>C | 1 | 0 | [16] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Pathogenic |
| T60I | Exon 2 | c.179 C>T | 1 | NA | [17] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Pathogenic | |
| G72R | Exon 3 | c.214 G>A | 1 | NA | [18] | DM | Possibly damaging/deleterious | Yes | No/possible | Yes | Pathogenic | |
| L77P | Exon 3 | c.230 T>C | 1 | NA | [19] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Pathogenic | |
| G81C | Exon 3 | c.241 G>T | 1 | 0 | [20] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Pathogenic | |
| G147D | Exon 4 | c.440 G>A | 1 | 0 | Unknown | — | Possibly damaging/deleterious | No | No/no | — | Unknown significant | |
| T206M | Exon 6 | c.617 C>T | 1 | NA | [21] | DM | Possibly damaging/deleterious | No | No/possible | Yes | Pathogenic | |
| G223S | Exon 6 | c.667 G>A | 2 | 0 | [21–22] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Pathogenic | |
| T228M | Exon 7 | c.683 C>T | 4 | 0 | [23] | DM | Possibly damaging/deleterious | No | Possible/possible | Yes | Pathogenic | |
| Q239R | Exon 7 | c.716 A>G | 1 | 0 | [24] | DM | Benign/tolerated | No | Possible/no | No | Likely pathogenic | |
| N254D | Exon 7 | c.760 A>G | 1 | 0 | Unknown | — | Possibly damaging/deleterious | No | Possible/no | — | Unknown significant | |
| L324P | Exon 8 | c.971 T>C | 1 | NA | [25] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Likely pathogenic | |
| S336X | Exon 8 | c.1,007 C>A | 1 | 0 | [16–20] | DM | Possibly damaging/deleterious | No | Possible/possible | — | Pathogenic | |
| R377H | Exon 9 | c.1,130 G>A | 1 | 0 | [19] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Likely pathogenic | |
| R377S | Exon 9 | c.1,129 C>A | 2 | NA | [16] | DM | Possibly damaging/deleterious | Yes | No/possible | Yes | Pathogenic | |
| S383L | Exon 9 | c.1,148 C>T | 1 | NA | [26] | DM | Possibly damaging/deleterious | No | No/possible | No | Pathogenic | |
| R392C | Exon 9 | c.1,174 C>T | 1 | 0 | [27] | DM | Possibly damaging/deleterious | No | Possible/possible | No | Likely pathogenic | |
| A454V | Exon 10 | c.1,361 C>T | 1 | NA | [27] | DM | Possibly damaging/deleterious | Yes | No/possible | Yes | Pathogenic | |
| E5-6 deletion | Exon 5-6 | — | 1 | NA | [16] | DM | — | — | — | — | Pathogenic | |
|
| ||||||||||||
| HNF4α | V251G | Exon 7 | c.752 T>G | 1 | 0 | Unknown | — | Possibly damaging/deleterious | Yes | Possible/no | — | Unknown significant |
|
| ||||||||||||
| HNF1α | A116V | Exon 2 | c.347 C>T | 1 | NA | [24] | DM | Possibly damaging/deleterious | Yes | Possible/possible | Yes | Pathogenic |
| R131W | Exon 2 | c.391 C>T | 1 | 0 | [28] | DM | Possibly damaging/deleterious | Yes | No/possible | Yes | Pathogenic | |
| R271W | Exon 4 | c.811 C>T | 1 | NA | [29] | DM | Possibly damaging/deleterious | No | Possible/no | Yes | Pathogenic | |
|
| ||||||||||||
| HNF1β | Whole gene deletion | — | 1 | NA | [30] | DM | — | — | — | — | Pathogenic | |
Amino acid numbers and nucleotide changes are based on NCBI RefSeq NM_175914.3 and NP_787110.2 for HNF4α, NM_000162.3 and NP_000153.1 for GCK, and NM_000545.5 and NP_000536.5 for HNF1α. aBold font denotes novel missense mutations in diabetes-specific missense mutations. All changes were heterozygous. NA: not analyzed. Possible functional effects of identified variants, especially unknown (novel) variants, were identified with two web-based programs, PolyPhen 2 (http://genetics.bwh.harvard.edu/pph2/) and SIFT (http://sift.bii.a-star.edu.sg/www/SIFT_seq_submit2.html). Potential effects on splicing were evaluated with HSF (Human Splicing Finder; http://www.umd.be/HSF3/technicaltips.html). Clinical information was evaluated with HGMD professional (http://www.hgmd.cf.ac.uk/) and ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/). Sequence conservation was evaluated with HGMD professional (http://www.hgmd.cf.ac.uk/).