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Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the nondevelopment of the uterus. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and the 46 XX Karyotype. With advancements in reproductive techniques, women with MA having biological offspring is possible.
Genes and Location in Chromosome | Reference | Method Used | Associations |
---|---|---|---|
MEFV and IL-32-16p13.3 CMTM7-3p22.3 CCR4 3p22.3 |
[11] | CGH and RT-qPCR | IL32 and MEFV gene mutations associated with Mediterranean fever. MRKHS |
BAZ2B and SLC4A10-2q24.2 KLHL18-3p21.31 PIK3CD-1p36.22 TNK2-3q29 |
[12] | WGS | MRKHS |
LAMC1-1q25.3 RARA-17q21.2 HOXA10-7p15.2 PAX2-10q24–25 MMP14 and LRP10-14q11.2 |
[10] | WES, confirmed by Sanger sequencing | MRKHS |
IFTP57, HHLA2 and MYH15-3q13.13 PLA2R1-2q23-q24 ITGB6 and RBMS1-2q24.2 |
[13] | SNP microarray analysis | MRKHS |
LRP10-14q11.2 FRAS1-4q21.21 CC2D2A-4p15.32 KIF14-1q32.1 RSPO4-20p13 MKKS-20p12.2 NPHP3-3q22.1 DYNC2H1-11q22.3 SPECC1L-22q11 VWF-12p13.31 |
[14] | WES | MRKHS |
TBC1D1-4p14 KMT2D-12q13.12 HOXD3-2q31-37 DLG5-10q22.3 GLI3-7p14.1 HIRA-22q11.21 GATA3-10p14 LIFR-5p13.1 CLIP1-12q24.31 |
[15] | Sanger sequencing | MRKHS |
PRKX-Xp22.33 HOXC8-12q13.13 |
[16] | RT-qPCR | MRKHS, Urinary malformations, skeletal malformations, and/or hearing defects. |
MUC1-1q22 | [16][17] | Array analysis, RT-qPCR | MRKHS |
RBM8A-1q21 | [18][19][20][21][22] | Array CGH, MLPA | TAR syndrome (thrombocytopenia, absence of radius) [18][19][20][21] |
WNT9B-17q21 | [9][10][21][23][24][25][26] | Array CGH, WES | MA, renal abnormalities, and cervicothoracic somite dysplasia [9] |
TBX6-16p11.2 | [9][10][14][20][21][22][27][28][29][30][31] | Array CGH. WES | Autism spectrum disorders, neurological disorders, unaffected persons [21] |
ACTR3B-Pseudogenes chromosomes 2, 4, 10, 16, 22 and Y | [25] | WES | MA |
LHX1-17q12 | [18][19][21][26][27][28][32][33][34][35][36][37][38][39][40] | Array CGH, gene sequencing | MA, Anomalies in the body axis formation [21], diabetes [33], learning disability [33] |
TCF2/HNF1B-17q12 | [18][19][27][28][32][33][34][35][36][37][38][39][41][42] | Array CGH, DNA sequencing | MA, Renal cysts [21] diabetes [21][33], learning disability [33] |
TBX1-22q11 | [18][19][20][27][43][44][45][46] | Array CGH, FISH, MLPA | DiGeorge syndrome, heart defect, hypocalcemia, immunodeficiency, typical facial malformations, cognitive and behavioral disorders |
WNT4-1p36.12 | [10][38][47][48][49] | PCR sequencing, CGH | Hyperandrogenism (Atypical MRKHS), Gonadal dysgenesis |
GREB1L-18q11.1-q11.2 | [16][25][50][51][52] | WES, CGH | MRKHS type 2 with kidney abnormalities, Twins discordant for MRKHS [16] |
DOCK4-7q31.1 | [14][35] | MRKHS | |
ZNF277-7q31.1 | [35] | MRKHS | |
DACT1-14q23.1 | [53] | MRKHS | |
DLGH1-3q29 | [54] | Direct sequencing | Unilateral agenesis, pelvic kidney |
OXTR-3p25.3 | [55] | DNA sequence analysis | MRKHS |
ESR1-6q25 | [56] | DNA sequence analysis | MRKHS |
WT1-11p13 | [57] | PCR | |
GATA4-8p23.1 | [57] | PCR | |
EMX2-10q26 | [9][58][59] | Sequence analysis | MRKHS, other Müllerian fusion abnormalities |
SHOX-Pseudoautosomal region Xp22. 3 | [10][60][61] | CGH | MRKHS |
PBX1-1q23.3 | [62] | MRKHS | |
PAX8-2q14.1 | [9][25][60][63] | Array CGH. WES | Mutations have been associated with thyroid dysgenesis, thyroid follicular carcinomas, and atypical follicular thyroid adenomas [64], MRKHS |
Chromosome Number | Mechanism [Reference] | Possible Gene Involved |
---|---|---|
1 | 1q31.1 Duplication (size 0.4 Mb) [27] 1q44 Deletion (size 0.32 Mb) [20][119] 1p36.12 mutations 1p36.21 deletion [119] Mutation p.(Glu226Gly) [49] Mutation c.1026C>T [45] Mutation p.(Arg83Cys) [120] Mutation c.35C>T p.(Leu12Pro) [121] Mutation c.483C>T [122] Mutation c.697G>A p.(Ala233Thr) [47] Mutation g.200583493A>T [14] 1q21 Deletion (size 0.4 Mb to 4.6 Mb) [18][20][119] 1q21 Duplication (size 0.26 Mb to 0.36 Mb) [19][20] |
1. KIF14 [14] 2. WNT4 is responsible for sex determination and affects the invagination of coelomic epithelial cells [97]. WNT4 mutation inhibits repression of ovarian steroid enzymes and causes abnormal expression of 17α hydroxylase and hyperandrogenism [47] 3. OR4M2, ZNF816 and PDE11A [119] |
2 | 2p14 Duplication (size-0.23 Mb) [18] 2p14 Mutation c.1315G>A, p.Ala439Thr [25] 2p23.1 Duplication (size-0.21 Mb) [27] 2p24 Deletion (size-4.6 Mb) [27] 2q11.2 Duplication (size-1.3 Mb) [27] 2q24.2 Duplication [13] 2q13 Deletion (size-0.12 Mb) [18] |
1. The PAX8 gene encodes a homeodomain signaling molecule, strongly expressed in the MD [123]. 2. Duplication at 2q24.2 of proband MRKHS involved PLA2R1, ITGB6 and RBMS1 |
3 | 3p21 Duplication 0.10 Mb [32] 3p21 Mutation c.861G>A [122] 3q13 Duplication at 3q13. [13] 3q29 Deletion 0.05 Mb [32] Mutation g.132403615G>A [14] |
1. WNT7A encodes secreted signaling proteins, and is involved in the development of the anterior–posterior axis in the female reproductive tract. Coded proteins are responsible for patterning during embryogenesis. Their role in MA is uncertain. 2. May involve DLGH1, OXTR, NPHP3 |
4 | 4q28 Deletion 0.11 Mb [32] 4q32 Deletion 0.34 Mb [32] 4q35.2 Deletion 1.1 Mb [26] Mutation g79204031G>A and g.15542618C>T [14] |
1. FRAS1 (g79204031G>A) [14] 2. CC2D2A (g.15542618C>T) [14] |
5 | 5p11 Deletion 0.40 Mb [34] 5q14.3 Deletion 0.40 Mb [34] |
|
6 | 6p21 Duplication 0.17 Mb [32] 6q25.1 Duplication 0.42 Mb [32] 6q25.2 Duplication 0.44 Mb [32] 6q11.1 Duplication 0.41 Mb [34] |
|
7 | 7p15.2 Hypomethylation [124] 7p14 Duplication 1.75 Mb [32] 7q31.2 Deletion 1.8 Mb [26] Mutation g111503593C>T [14] |
1. HOXA5 is a transcriptional regulator of p53 and progesterone receptor (PGR). Hypomethylation leads to overexpression, which causes overexpression of PGR [125]. Ectopic HOXA5 expression at the 5′end of the cluster might prevent normal differentiation of the MD or even regression. 2. It most likely involves Abdominal B (AbdB) homeobox genes (HOX-A9, A10, A11, and A13), required for differentiation and segmental patterning of MD [126] 3. HOXA9 is expressed in the region that becomes the oviduct [127]. Ectopic expression of HOXA5 or HOXA9 inhibits MD differentiation [128]. 4. DOCK4 |
8 | 8p23.1 Hypomethylation [57] 8p23.1 Activating mutations [124] |
GATA binding protein 4 promotes AMH production and regulates sex determination and differentiation [57]. Overproduction of AMH leads to MA. |
10 | 10q24 Duplication 0.05 Mb [32] | |
11 | 11p11.12 Deletion 0.76 Mb (45) 11p 13 Hypomethylation [57] 11p 13 Activating mutation [124] Mutation g.102985987C>T [14] |
1. WT1 is a regulatory factor important for the transcription of anti-Müllerian hormone (AMH) genes. It promotes AMH expression and regulates sex determination and differentiation [57]. Activating the mutation of the gene for the AMH receptor, or the receptor, causes excessive production of AMH, leading to MRKHS [124] 2. DYNC2H1 |
12 | 12q13.13 Duplication [13] 12q23 Duplication 0.16 Mb [32] 12q24 Duplication 0.12 Mb [32] Mutation g.6085324G>A [14] |
VWF |
13 | 13q21 Deletion 0.41 Mb [26] | |
14 | 14q32.33 Deletion 0.46 Mb [34] 14q32.33 mutation g.23345412G>A [14] |
LRP10 |
15 | 15q21.1 Deletion 0.28 Mb [34] 15q26.3 Deletion 0.54 Mb [26] Deletions at 15q11.2 [119] |
|
16 | 16p13.3 Increased expression [11] 16q11.2 Duplication 0.20 Mb [27] 16p11.2 Deletion (size 0.55 Mb to 0.6 Mb) [27] Splice site mutation c.622-2A>T (g.30100162 T>A) [28] Mutation c.484G>A(rs56098093) p.Gly162Ser [28] Mutation c.815G>A p.Arg272Gln [28] Mutation c.815G>A [26] |
1. Genes for IL32 and MEFV. 2. TBX6 is involved in paraxial mesoderm formation and somitogenesis in human embryos [129]. Deletion induces MRKHS due to the loss of the transcription factor. |
17 | 17q12 Deletion (size 1.2 to 1.9 Mb) [13][18][19][20][27][32][34] 17q12 Missense mutation of LHX1 [18][33] c.790C>G p.(Arg264Gly) c. c.25dup p.(Arg9Lysfs*25) 17q21-22 mutations c.28G>T p.Ala10Ser c.205C>T, p.Arg69Trp [25] c.*158C>T 17q21-22 Five Missense mutations [26] c.472C>G p.(Gln158Glu) c.665G>A p.(Arg222His) c.722G>A p.(Arg24His) c.974G>A p.(Arg325His) c.1029C>A p.(Cys343*) |
1. Involves the LHX1(LIM homeobox protein 1) gene, which is a transcription factor necessary for the formation of the Müllerian duct-derived uterine and vaginal epithelia [92]. 2. HNF1B is [Pit–Oct–Unc homeodomain-containing transcription factor that is frequently expressed in the Müllerian duct during development [130]. It positively regulates the expression of LHX1, PAX2, and WNT9B [131]. 3. Involves mutations in WNT9B, which acts upstream of another Wnt4. It is responsible for the caudal extension of the Müllerian duct and the organization of the urogenital system [98]. |
18 | 18q23 Duplication 0.20 Mb [34] 18p Deletion [132] 18q11.1-q11.2 mutation c.4665T>A, p.Tyr1555 |
GREB1L is a target gene in the retinoic acid signaling pathway, which is highly expressed in the developing fetal human kidney and involved in the early metanephros and genital development [133]. |
19 | 19q13.31 deletion [119] | OR2T2 [119] |
20 | 20q13.12 Deletion Mutations g.941074G>A and g.10393439C>A [14] |
1. WISP2 is significant in smooth muscle cell proliferation and migration, and is induced by estrogen in the uterus [134]. Estrogen regulates AMH expression levels [135], and overexposure to estrogen during development activates AMH promotors [124]. 2. RSPO4 3. MKKS |
22 | 22q11 Deletion (size 0.39 Mb to 2.6 Mb) [27][33][43][45] Duplication (0.6 Mb–3.5 Mb) [19][33][136] Mutations g.24720297G>A and g.24718408G>A [14] |
1. TBX1 2. SPECC1L |
X | Xp11.1 Deletion 0.12 Mb [32] Xp11.3 Duplication 0.24 Mb [32] Xp22 Duplication (0.07 to 0.36) [16][18][19][20][137] Xq21.31 Deletion 1 Mb [138] Xq deletion [139] Xq22.3 Duplication 0.09 Mb [32] Xq22.3 Microdeletion at Xp22.33 [13] |
1. May involve the PRKX gene, encoding for a serine/threonine kinase implicated in renal epithelium morphogenesis [16]. 2. May involve the SHOX gene, which encodes a transcription factor responsible for skeletal growth. The exact mechanism is unknown. |
8,13 | t(8;13) (q12;q14) translocation | Translocation causes MRKHSS with or without renal hypoplasia [140]. |
t(8;13)(q22.1;q32.1) translocation | Translocation causes MRKHS with limb, breast, and urinary functional defects [141] | |
3,16 | t(3;16) (p22.3;p13.3) translocation | Translocation causes MRKHS [11][73] |
7,14 | t(7;14)(q32;q32) translocation | Translocation seen in MRKHS [73] |
2, 4, 10, 16, 22 and Y | c.1066G>A, p.Gly356Arg [25] | ACTR3B encodes a member of the actin-related proteins and plays a role in the organization of the actin cytoskeleton [142]. ACTR3B can have pseudogenes in more than one chromosome. |