Table 3. Summary of reported patients harboring sequence variations and deletions affecting MAMLD1 gene a .
| Mutation number, Reference | Karyotype, Assigned sex | MAMLD1 gene mutation | Genital anatomy | Gonadal function, Gonadal histology | Adrenal function | Family, Other data | Present in controls? | Functional/additional studies | Additional phenotype Other genetic studies |
|---|---|---|---|---|---|---|---|---|---|
| 1. Metwalley and Farghaly, 2012 [8] | ?, 1 male | c.325delG | Distal hypospadias with chordee and normal testes | Profile consistant with X-linked congenital adrenal hypoplasia | - | Egyptian origin | - | - | Mutation in DAX-1 (R327P) |
| 2. Kalfa et al., 2012 [6] | 46,XY, 1 male | c.428C>A, S143X | Scrotal hypospadias, microphallus, intrascrotaltestis | Normal T, LH, FSH, AMH, Inhibin | - | Mother heteterozygous, uncle severe hypospadias, maternal cousin severe hypospadias (not available for testing) | - | Loss of transactivation activity on Hes3 | N: AR, SRD5A2 |
| 3. Kalfa et al., 2008 [4] | ?, 1 male | c.546del, E182fsX121 | Proximal hypospadias, inguinal testis | NA | Normal | - | - | - | |
| 3. Kalfa et al., 2008 [4] | ?, 1 male | c.546del, E182fsX121 | Penoscrotal hypospadias with chordee, intrascrotal testis | NA | Normal | - | - | - | |
| 4. Fukami et al., 2006 [3]; Fukami et al., 2008 [14] | ?, 2 males, half brothers | c.589G>T, E197X rs121909493 | 1st: penoscrotal hypospadias, inguinal testes; 2nd: penoscrotal hypospadias, scrotal testes; penis 2.5 cm | All normal, FSH low | Normal | Japanese origin. Mother heterozygous | Absent in 150 Japanese males | Causes non-mediated RNA decay. Reduced leukocyte transcripts. No transactivation activity on Hes3, reduced protein expression | N: AR, SRD5A2 |
| 5. Fukami et al., 2006 [3]; Fukami et al., 2008 [14] | ?, 1 male | c.808C>T, Q270X rs121909494 | Penoscrotal hypospadias, scrotal testes; penis 2 cm | Normal | Normal | Japanese origin. Mother not studied | Absent in 150 Japanese males | Causes non-mediated RNA decay. Reduced leukocyte transcripts. No transactivation activity on Hes3, increased protein expression | N: AR, SRD5A2 |
| 6. Kalfa et al., 2012 [6] | 46,XY (1/70), 1 male | c.1041C>A, H347Q, rs62641609 | Posterior hypospadias, microphallus | - | - | - | - | - | - |
| 7. Kalfa et al., 2012 [6] | 46,XY, 5 males | c.1075C>T, P359S, rs41313406 | Non-syndromic DSD | - | - | - | - | - | - |
| 7. Fukami et al., 2006 [3]; Fukami et al., 2008 [14] | ?, 1 male | c.1075C>T, P359S, rs41313406 | Hypospadias | NA | NA | Swedish origin. Absent in brother and nephew with same phenotype | In 8/110 Swedish Controls | Transactivation activity on Hes3 similar to WT | - |
| 7. Chen et al., 2010 [7] | ?, 11 males | c.1075C>T, P359S, rs41313406 | Hypospadias | - | - | - | No | Weak association with hypospadias by screening in a case-control SNP-genotyping study | - |
| 7. Kalfa et al., 2011 [5] | ?, 17 males (17/150) | c.1075C>T, P359S, rs41313406 | Hypospadias | - | - | - | Yes | Transactivation activity on Hes3 similar to WT | - |
| 8. Lim et al., 2013 [31] | ?, 1 male | c.1141C>T, R371X | Normal | - | - | - | Present in 1 control | Detected by exome sequencing in a study on autism | - |
| 9. Kalfa et al., 2012 [6] | 46,XY, 1 male | c.1151C>T, P384L | Penile hypospadias, microphallus, intrascrotal testis | Slightly low LH, FSH. Low T, AMH, inhibin | - | Maternal diabetes | - | Reduced transactivation activity on Hes3 | N: AR, SRD5A2 |
| 10. Kalfa et al., 2008 [4] | ?, 1 male | c.1514T>C, V505A, rs61740566 | Isolated proximal hypospadias, intrascrotal testis | NA | NA | - | - | - | - |
| 10. Zhang et al., 2010 [18] | ?, Neandertal | c.1514T>C, V505A, rs61740566 | - | - | - | - | - | - | |
| 10. Brandao et al., 2011 [11] | 46,XX DSD (GD), 1 female | V505A, homozygote, rs61740566, (GOF) | Primary amenorrhea, no breast development, eunuchoid habitus, absence hirsutism, Tanner IV pubic hair, clitoromegaly, 2 perineal openings, unpalpable gonads. Bilateral streak gonads, small uterus, bilateral Fallopian tubes. | FSH eleated, normal LH, Prog, 17OH-Prog, androstenedione, T non increasing after hCG stimulation. Histology: absence of left gonad; fallopian tubes and a dysgenetic right gonad with hilar cell hyperplasia and persistence of Wolffian rests | - | Parents are first cousins | Absent in 190 normal alleles | Transactivation activity on Hes3 and Hes7 higher than WT | N: FOXL2, BMP15, STRA8, Nanos1, Nanos2, NR5A1, Wnt4 |
| 10. Chen et al., 2010 [7] | ?, 1 Male | c.1514T>C, V505A, rs61740566 | Hypospadias | - | - | - | Yes | Not located in the conserved site of the protein | - |
| 11. Fukami et al., 2006 [3]; Fukami et al., 2008 [14] | ?, 2 male brothers | c.1739A>G, Q580R | Female genitalia | NA | NA | Italian origin. Absent in nephew with same phenotype | Absent in 200 European controls | Transactivation activity on Hes3 equal or higher than WT | - |
| 12. Chen et al., 2010 [7] | ?, 1 male | c.1804C>A, Q602K, rs142908182 | Severe hypospadias | - | - | - | No | - | - |
| 13. Chen et al., 2010 [7] | ?, 3 males | c.604ins3Q | Penoscrotal hypospadias, micropenis/chordee | - | - | - | Yes | - | - |
| 14. Kalfa et al., 2008 [4] | ?, 1 male | c.1810ins3Q, 614ins3Q | Isolated coronal hypospadias, intrascrotal testes | NA | NA | - | - | - | - |
| 15. Fukami et al., 2006 [3]; Fukami et al., 2008 [14] | ?, 3 patients | c.1985A>G, N662S, rs2073043 | DSD | NA | NA | 2 Japanese and 1 European origin | In 4 Japanese controls | Transactivation activity on Hes3 similar to WT | - |
| 15. Chen et al., 2010 [7] | ?, 11 males | c.1985A>G, N662S, rs2073043 | Hypospadias ranging from perineal to cleaved prepuce | - | - | - | No | Association with hypospadias by screening in a case-control SNP-genotyping study | - |
| 15. Kalfa et al., 2012 [6] | ? | c.1985A>G, N662S, rs2073043 | Non-syndromic DSD | - | - | - | - | - | - |
| 15. Kalfa et al., 2011 [5] | ?, males (22/150) | c.1985A>G, N662S, rs2073043 | Hypospadias | - | - | - | Yes | Transactivation activity on Hes3 similar to WT | - |
| 7 + 15. Kalfa et al., 2011 [5] | ?, males (16/150) | P359S+N662S | Hypospadias | - | - | - | Yes | Transactivation activity on Hes3 similar to WT | - |
| 7 + 15. Kalfa et al., 2012 [6] | ?, 14 males | P359S+N662S | 3 cases: penile posterior hypospadias, cryptorchidism; 5 cases: hypospadias, microphallus; 6 cases: cryptorchidism, microphallus | - | - | - | - | Combined data: incidence of P359S-N662S is higher in DSDs | - |
| 7 + 15. Gaspari et al., 2011 [12] | ?, 1 male | P359S+N662S | Right cryptorchidism, penis 1.5 cm (2.9 mo) | Normal androgen production | - | French with Mediterranian origin | - | Study to evaluate effect of prenatal exposure to environmental endocrine disruptors | N: AR, SRD5A2, NR5A1 |
| 16. Ruiz-Arana et al., 2015 [10] | 46,XY, (1/35 DSD ambiguous genitalia), 1 female | c.2030C>T, P677L | Complete gonadal dysgenesis, external female genitalia, no gonads detected, uterus present, primary amenorrhea (13y). | FSH and LH elevated at diagnosis, estrogen low, testosterone normal | - | Mother heterozygous (normal phenotype), father WT. No family history of DSD | No | Abolished transactivation activity on Hes3 | N: SRY, NR5A1, WT1 |
| 17. Fukami et al., 2006 [3]; Fukami et al., 2008 [14] | ?, 1 male | c.2176C>T, R726X rs121909495 | Penoscrotal hypospadias, retractile testes, penis 1.2 cm | Normal | Normal | Japanese origin. Mother heterozygous. | Absent in 150 Japanese males | Causes non-mediated RNA decay. Reduced leukocyte transcripts. Transactivation activity on Hes3 similar to WT, protein expression similar to WT | N: AR, SRD5A2 |
| 18. Igarashi et al., 2015 [9] | 46,XY, 1 male (1/180) | c.2041-2A>G, K682fsX1070 | Penoscrotal hypospadias, scrotal testes | Normal T, LH and FSH (2y 11 m) | - | - | - | Reduced transactivation activity on Hes3. Reduced mutant protein expression. | - |
| 19. Chen et al., 2010 [7] | ?, male | c.2277C>T, D759D | Hypospadias | - | - | - | No | - | - |
| 20. Chen et al., 2010 [7] | ?, male | c.2284+8A>T | Hypospadias | - | - | - | No | - | - |
| 21. Hu et al., 1996 [1]; Laporte et al., 1997 [2] | 1 male, 46,XY | Microdeletion including MAMLD1-MTM1, 5’MAMLD1 gene deletion | Hypospadias, enlarged clitoris/micropenis, bifid scrotum, non- palpable testes. Introitus vagina and vaginal pouch. | Normal 17OHProgesterone, 21DOC, androstenedione, testosterone, dihydrotestosterone, FSH and LH levels | - | - | - | - | - |
| 22. Hu et al., 1996 [1]; Laporte et al., 1997 [2] | 1 male, 46,XY | Microdeletion including MAMLD1-MTM1, whole MAMLD1 gene deletion | Perineoscrotal hypospadias. Neuromuscular disorder | - | - | - | - | - | - |
| 23. Bartsch et al., 1999 [28] | 3 males: 2 babies and 1 fetus | Microdeletion including MAMLD1-MTM1, whole MAMLD1 gene deletion | 1st: abnormal genitalia (undescended right testis and glandular hypospadias) and extreme muscular hypotonia; 2nd: bilateral cryptorchidism, penile hypospadias and extreme muscular hypotonia; 3rd (terminated 13 WG): penile hypospadias. | - | - | Mother asthenic, low muscle power and irregular menses | - | - | - |
| 24. Tsai et al., 2005 [29] | 1 male | Microdeletion: deletion MAMLD1ex6-8-MTMR1ex1-2, resulting in a fusion MAMLD1-MTMR1 | Without DSD. Myotubular myopathy | - | - | Japanese origin | - | - | - |
| 25. Oliveira et al., 2013 [30] | 1 male | Complex rearrangement including the whole MAMLD1 gene and a fusion 5’MTM1-3’MAMLD1+MTM1 | Without DSD. Myotubular myopathy | - | - | - | - | - | - |
a the variants were named according to NM_005491.4.
N: normal sequence; NA: not analyzed; ?/-: unknown; GD: gonadal dysgenesis; GOF: gain of function.