Alternative titles; symbols
HGNC Approved Gene Symbol: DHX37
SNOMEDCT: 53599007;
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38): 12:124,946,826-124,989,131 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | 46XY sex reversal 11 | 273250 | Autosomal dominant | 3 |
| Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies | 618731 | Autosomal recessive | 3 |
DHX37 is an RNA helicase that binds to a subset of glycine receptor (GLR)-alpha (see GLRA1, 138491) transcripts and regulates their splicing (Hirata et al., 2013).
By sequencing clones obtained from a size-fractionated fetal human brain cDNA library, Nagase et al. (2000) obtained a partial DHX37 clone, which they designated KIAA1517. The deduced protein contains at least 998 amino acids and shares significant similarity with a C. elegans ATP-dependent RNA helicase. RT-PCR ELISA detected robust KIAA1517 expression in all adult and fetal tissues and all specific adult brain regions examined.
Using immunohistochemistry, da Silva et al. (2019) characterized DHX37 expression in testes from newborns, children, and adults. DHX37 was expressed in fibroblasts, endothelial cells, and epithelial cells of epididymis, as well as in Leydig cell cytoplasm and in germ cells at different stages of maturation. The authors found that DHX37 expression in spermatogonia is characterized by a regular perinuclear halo pattern in both newborns and adults, and noted that this pattern of staining differed from the granular cytoplasmic staining seen in Leydig cells and during other stages of maturation of germ cells. A progressive condensation of protein around the nucleus was observed, as cells differentiated from spermatocytes to spermatids, generating a localized paranuclear dot-like pattern. There was no staining in spermatozoa. Rare Sertoli cells displayed a weak and focal cytoplasmic stain.
McElreavey et al. (2020) observed that DHX37 is expressed exclusively in somatic cell lineages of the mouse and human gonad during testis determination and development. The highest concentration of the protein was at the nuclear membrane, although protein was also observed in the cytoplasm and in the nucleolus of some cells. Analysis of protein expression in different tissues from adults revealed that DHX37 is highly localized at the nuclear membrane in multiple human and mouse cell lines. Although expression was not observed in germ cells in fetal gonads, in adult human testes the protein was mainly localized in spermatogonia. In addition, single-cell expression analysis of Nr5a1 (184757)-positive somatic cells of the developing XY mouse gonad showed that Dhx37 is coexpressed with the sex-determining gene Sox9 (608160) in a proportion of cells.
By radiation hybrid analysis, Nagase et al. (2000) mapped the DHX37 gene to chromosome 12.
Hartz (2017) mapped the DHX37 gene to chromosome 12q24.31 based on an alignment of the DHX37 sequence (GenBank AB040950) with the genomic sequence (GRCh38).
Neurodevelopmental Disorder with Brain Anomalies and with or without Vertebral or Cardiac Anomalies
By whole-exome sequencing, Karaca et al. (2015) identified a homozygous missense mutation in the DHX37 gene (N419K; 617362.0001) in a boy with neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies (NEDBAVC; 618731). By exome sequencing, Paine et al. (2019) identified 2 additional patients with NEDBAVC who were compound heterozygous for mutations in the DHX37 gene (617362.0002-617362.0005). In 2 other patients, Paine et al. (2019) identified heterozygous mutations in the DHX37 gene; one mutation was proven to be de novo and the other was not found in the patient's mother but no sample from the father was available for study.
46,XY Sex Reversal 11
By genetic analysis of 87 patients with 46,XY sex reversal (SRXY11; 273250), da Silva et al. (2019) identified 17 patients from 11 unrelated families of varying ethnicities who were heterozygous for 4 different missense mutations in the DHX37 gene: R308Q (617362.0006) in 4 patients from 2 Brazilian families and 3 sporadic Chinese American patients; R674W (617362.0007) in 3 patients from an Argentinian family, 2 from a Chilean family, and 2 sporadic Brazilian patients; S595F (617362.0008) in a Brazilian aunt and nephew; and T304M (617362.0009) in a Brazilian woman. All 4 variants were located in the DHX37 helicase core region.
From a cohort of 145 patients of European ancestry with 46,XY disorders of sex differentiation (DSD), McElreavey et al. (2020) identified 13 patients who were heterozygous for missense mutations in the DHX37 gene, including the recurrent R308Q (617362.0006) and T304M (617362.0009) mutations and 6 other variants (see, e.g., R674Q, 617362.0010). All but 1 clustered within the functional RecA1 and RecA2 domains of the protein and involved highly conserved amino acids.
In 52 adult 46,XY women, Buonocore et al. (2019) sequenced the NR5A1 gene (184757) and analyzed targeted panels of DSD-associated and candidate genes. A likely pathogenic variant was identified in 16 (30.8%) of the patients in the cohort, including 4 patients who were designated as having partially virilized DSD and who had a heterozygous mutation in the DHX37 gene: the recurrent R308Q substitution was detected in 3 patients who had been previously reported by McElreavey et al. (2020), and a T477M substitution in the remaining patient, who exhibited mild virilization and an absent uterus.
Hirata et al. (2013) identified a recessive mutation, termed nig1, in breeding colony zebrafish. At 2 days postfertilization, mutant zebrafish responded to touch with a dorsal bend prior to swimming, in contrast with a turn to the lateral side prior to swimming exhibited by wildtype zebrafish. The mutant response was similar to those made by wildtype fish in response to strychnine, a GLR antagonist, suggesting that the mutation interfered with glycinergic transmission, a hypothesis supported by physiologic measurements. Western blot analysis showed reduced levels of Glra subunits in mutant zebrafish compared with wildtype. Genetic mapping revealed a lys489-to-pro (K489P) mutation in the Dhx37 gene in the mutant fish. Mutant fish injected with wildtype Dhx37 RNA exhibited normal escape behavior, whereas a quarter of wildtype fish injected with K489P Dhx37 RNA exhibited behavior similar to mutant fish. Quantitative PCR and Northern blot analyses indicated decreased expression of Glra1, Glra3 (600421), and Glra4, but not Glra2 (305990), in mutant zebrafish. Normal escape behavior was restored by overexpression of Glra subunits in Dhx37 mutant zebrafish. Hirata et al. (2013) concluded that DHX37 is required for biogenesis of a subset of GLRA mRNAs and thereby regulates glycinergic synaptic transmission.
By whole-exome sequencing in a boy (BAB4434), born to consanguineous parents, with neurodevelopmental disorder with brain anomalies (NEDBAVC; 618731), Karaca et al. (2015) identified homozygosity for a c.1257C-A transversion (c.1257C-A, NM_032656) in the DHX37 gene, resulting in an asn419-to-lys (N419K) substitution. Both parents were carriers. Paine et al. (2019) also reported this patient (individual 1).
Hamosh (2019) noted that the N419K variant was absent from the gnomAD database (December 28, 2019).
By exome sequencing in an Italian woman (individual 2) with neurodevelopmental disorder with brain and vertebral anomalies (NEDBAVC; 618731), Paine et al. (2019) identified compound heterozygous missense mutations in the DHX37 gene: a c.2191G-A transition (c.2191G-A, NM_032656.3), resulting in a val731-to-met (V731M) substitution, and a c.1399C-T transition, resulting in a leu467-to-val (L467V; 617362.0003) substitution. The unaffected parents were each heterozygous for one of the mutations, and 2 unaffected sisters were heterozygous for the V731M mutation.
Hamosh (2019) noted that the V731M variant was found in heterozygous state in 2 Europeans and 1 African in the gnomAD database, for a highest allele frequency of 0.00008153. The L467V variant was detected in heterozygous state in 38 Europeans, 8 Latinos, and 2 others in gnomAD, for a highest allele frequency of 0.0002952 (December 28, 2019).
For discussion of the c.1399C-T transition (c.1399C-T, NM_032656.3) in the DHX37 gene, resulting in a leu467-to-val (L467V) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with brain anomalies and scoliosis (NEDBAVC; 618731) by Paine et al. (2019), see 617362.0002.
In an American boy with neurodevelopmental disorder with brain and cardiac anomalies (NEDBAVC; 618731), Paine et al. (2019) identified compound heterozygous mutations in the DHX37 gene: a c.278G-A transition (c.278G-A, NM_032656.3), resulting in an arg93-to-gln (R93Q) substitution, and a c.499_500delGAinsTC mutation, resulting in a glu167-to-ser (E167S; 617362.0005) substitution. The parents were each heterozygous for one of the mutations.
Hamosh (2019) noted that the R93Q variant was found in 9 Latinos, 1 other, and 5 Europeans in the gnomAD database, for a highest allele frequency of 0.0002542. The E167S variant was not present in gnomAD (December 28, 2019).
For discussion of the c.499_500delGAinsTC mutation (c.499_500delGAinsTC, NM_032656.4) in the DHX37 gene, resulting in a glu167-to-ser (E167S) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with brain and cardiac anomalies by Paine et al. (2019), see 617362.0004. (In the article by Paine et al. (2019), this variant is listed as E167S in Table 1 but as c.500_501delinsTC; E167A in the text and a supplemental table; Paine (2020) confirmed that the correct mutation is c.499_500delGAinsTC; E167S.)
In 4 patients from 2 unrelated Brazilian families (F1 and F2) and 3 sporadic Chinese American patients (F6, F7 and F8) with gonadal dysgenesis (SRXY11; 273250), da Silva et al. (2019) identified heterozygosity for a c.923G-A transition (c.923G-A, NM_032656.3) in the DHX37 gene, resulting in an arg308-to-gln (R308Q) substitution at a highly conserved residue within motif 1a of the helicase ATP-binding domain. A founder effect was ruled out in the 2 Brazilian families. The R308Q variant was not found in the 1000 Genomes Project, ExAC, ESP6500, or ABraOM databases, but was present at low minor allele frequency (0.00006677) in the gnomAD database, in non-Finnish Europeans. Segregation analysis showed a sex-limited autosomal dominant pattern with maternal inheritance in F2, whereas confirmed paternity revealed a de novo status of the R308Q variant in 2 of the sporadic cases (F6 and F8). In F1, the R308Q variant was present in the asymptomatic father, suggesting an autosomal dominant pattern of inheritance with incomplete penetrance. Six of the patients were diagnosed with testicular regression syndrome and 1 with partial gonadal dysgenesis; 4 were reared as male individuals and 2 as female, and 1 transitioned from male to female.
In 4 46,XY patients of European ancestry, including 3 reared as female, of whom 2 (patients 7 and 8) were diagnosed with 46,XY disorder of sex differentiation and 1 (patient 9) with gonadal dysgenesis, as well as 1 patient (patient 12) reared as male with a diagnosis of testicular regression syndrome, McElreavey et al. (2020) identified heterozygosity for the R308Q mutation in the DHX37 gene. The mutation arose de novo in patient 12; segregation was unknown in the 3 other patients.
In 3 patients from an Argentinian family (F4) and 2 from a Chilean family (F3), as well as 2 sporadic Brazilian patients (F10 and F11) with gonadal dysgenesis (SRXY11; 273250), da Silva et al. (2019) identified heterozygosity for a c.2020C-T transition (c.2020C-T, NM_032656.3) in the DHX37 gene, resulting in an arg674-to-trp (R674W) substitution at a highly conserved residue within motif VI of the helicase superfamily C-terminal domain. The R674W variant was not found in the 1000 Genomes Project, ABraOM, ESP6500, ExAC, or gnomAD databases. Segregation analysis showed a sex-limited autosomal dominant pattern with maternal inheritance in F3, F4, and F11; DNA was not available from the deceased parents in F10. Five of the patients were diagnosed with testicular regression syndrome and 2 with partial gonadal dysgenesis; 5 were reared as male individuals and 1 as female, and 1 transitioned from male to female.
In a Brazilian aunt and nephew (F5) with gonadal dysgenesis (SRXY11; 273250), da Silva et al. (2019) identified heterozygosity for a c.1784C-T transition (c.1784C-T, NM_032656.3) in the DHX37 gene, resulting in a ser595-to-phe (S595F) substitution at a highly conserved residue within the helicase core region. The R674W variant was not found in the South Asian population of the 1000 Genomes Project, or in the ABraOM, ESP6500, ExAC, or gnomAD databases. Both affected individuals inherited the mutation from an unaffected mother, consistent with a sex-limited autosomal dominant pattern. The aunt was reared female, with a diagnosis of partial gonadal dysgenesis, whereas the nephew was reared male, with a diagnosis of testicular regression syndrome.
In a 46,XY Brazilian woman (F9) with gonadal dysgenesis (SRXY11; 273250), da Silva et al. (2019) identified heterozygosity for a c.911C-T transition (c.911C-T, NM_032656.3) in the DHX37 gene, resulting in a thr304-to-met (T304M) substitution at a highly conserved residue within the helicase ATP-binding domain. The T304M variant was not found in the 1000 Genomes Project, ABraOM, ESP6500, ExAC, or gnomAD databases.
In 2 unrelated 46,XY female patients (patients 4 and 5) with a diagnosis of gonadal dysgenesis, McElreavey et al. (2020) identified heterozygosity for the T304M mutation in the DHX37 gene. The mutation was inherited from an unaffected mother in patient 4, and arose de novo in patient 5.
In 2 unrelated 46,XY female patients (patients 1 and 2) with gonadal dysgenesis (SRXY11; 273250) of European ancestry, McElreavey et al. (2020) identified heterozygosity for a c.2021G-A transition in the DHX37 gene, resulting in an arg674-to-gln (R674Q) substitution at a highly conserved residue within the RecA2 domain. The mutation arose de novo in 1 of the patients; inheritance was unknown in the other.
Buonocore, F., Clifford-Mobley, O., King, T. F. J., Striglioni, N., Man, E., Suntharalingham, J. P., del Valle, I., Lin, L., Lagos, C. F., Rumsby, G., Conway, G. S., Achermann, J. C. Next-generation sequencing reveals novel genetic variants (SRY, DMRT1, NR5A1, DHH, DHX37) in adults with 46,XY DSD. J. Endocr. Soc. 3: 2341-2360, 2019. [PubMed: 31745530] [Full Text: https://doi.org/10.1210/js.2019-00306]
da Silva, T. E., Gomes, N. L., Lerario, A. M., Keegan, C. E., Nishi, M. Y., Carvalho, F. M., Vilain, E., Barseghyan, H., Martinez-Aguayo, A., Forclaz, M. V., Papazian, R., Pedroso de Paula, L. C., Costa, E. C., Carvalho, L. R., Jorge, A. A. L., Elias, F. M., Mitchell, R., Costa, E. M. F., Mendonca, B. B., Domenice, S. Genetic evidence of the association of DEAH-box helicase 37 defects with 46,XY gonadal dysgenesis spectrum. J. Clin. Endocr. Metab. 104: 5923-5934, 2019. [PubMed: 31287541] [Full Text: https://doi.org/10.1210/jc.2019-00984]
Hamosh, A. Personal Communication. Baltimore, Md. 12/28/2019.
Hartz, P. A. Personal Communication. Baltimore, Md. 2/23/2017.
Hirata, H., Ogino, K., Yamada, K., Leacock, S., Harvey, R. J. Defective escape behavior in DEAH-box RNA helicase mutants improved by restoring glycine receptor expression. J. Neurosci. 33: 14638-14644, 2013. [PubMed: 24027265] [Full Text: https://doi.org/10.1523/JNEUROSCI.1157-13.2013]
Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Akdemir, Z. C., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., and 52 others. Genes that affect brain structure and function identified by rare variant analyses of mendelian neurologic disease. Neuron 88: 499-513, 2015. [PubMed: 26539891] [Full Text: https://doi.org/10.1016/j.neuron.2015.09.048]
McElreavey, K., Jorgensen, A., Eozenou, C., Merel, T., Bignon-Topalovic, J., Tan, D. S., Houzelstein, D., Buonocore, F., Warr, N., Kay, R. G. G., Peycelon, M., Siffroi, J.-P., and 18 others. Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome. Genet. Med. 22: 150-159, 2020. [PubMed: 31337883] [Full Text: https://doi.org/10.1038/s41436-019-0606-y]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331] [Full Text: https://doi.org/10.1093/dnares/7.2.143]
Paine, I., Posey, J. E., Grochowski, C. M., Jhangiani, S. N., Rosenheck, S., Kleyner, R., Marmorale, T., Yoon, M., Wang, K., Robison, R., Cappuccio, G., Pinelli, M., and 42 others. Paralog studies augment gene discovery: DDX and DHX genes. Am. J. Hum. Genet. 105: 302-316, 2019. [PubMed: 31256877] [Full Text: https://doi.org/10.1016/j.ajhg.2019.06.001]
Paine, I. Personal Communication. Houston, Tx. 1/15/2020.