* 154235

MALE GERM CELL-ASSOCIATED KINASE; MAK


HGNC Approved Gene Symbol: MAK

Cytogenetic location: 6p24.2     Genomic coordinates (GRCh38): 6:10,762,723-10,838,539 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
6p24.2 Retinitis pigmentosa 62 614181 AR 3

TEXT

Cloning and Expression

Male germ cell-associated kinase is one of the protein kinases that was isolated by weak cross-hybridization with the v-ros (165020) protein kinase sequence (Matsushime et al., 1990). The gene encoding this kinase is expressed almost exclusively in testis, mainly in germ cells at and/or after the pachytene stage, as 66- and 60-kD proteins that form a distinct complex with cellular phosphoprotein p210. The p210 protein is sufficiently phosphorylated in vitro by the MAK gene product at serine and threonine residues. These results suggest that the MAK gene plays an important role in spermatogenesis.

Using mono- and polyclonal antibodies, Tucker et al. (2011) localized MAK to human retina. In photoreceptor cells, labeling was predominantly observed in the outer nuclear layer, axons, and inner segments. Outer segments that contained abundant rhodopsin (180380) did not show strong MAK expression, which was generally not observed distal to the connecting cilium. The localization of MAK to photoreceptor cells was also observed in the foveal cones, in which inner segments as well as the Henle fiber layer of axons were strongly positive. By Northern blot analysis of normal human retina, Tucker et al. (2011) detected the largest and most abundant MAK transcript to be slightly larger than 2,000 nucleotides in length; RT-PCR analysis followed by DNA sequencing revealed a novel 75-bp exon not previously known to exist in humans, located between exons 11 and 12 of the longest previously published human MAK transcript. This 14-exon retinal transcript, in which the newly recognized exon was designated to be exon 12, contains 648 amino acids with a calculated molecular mass of 73.3 kD. RT-PCR analysis of human tissues showed that exon 12-containing MAK transcript is only expressed in retina.

Ozgul et al. (2011) performed PCR amplification of full-length MAK coding sequence from human retina and identified a photoreceptor-enriched alternative exon (exon 13), previously reported in mice (Omori et al., 2010), that corresponded to a 25-residue block of phylogenetic conservation. Expression analysis revealed that the longer isoform, including the alternative exon, is the predominant species in the retina, with barely detectable expression of the shorter isoform. In testis, the shorter isoform predominates, whereas the longer form is detectable at lower levels.


Gene Structure

Tucker et al. (2011) determined that the MAK gene contains 14 exons.


Mapping

Using a panel of DNA samples from an interspecific cross, Taketo et al. (1994) mapped the Mak gene to mouse chromosome 13 in an area situated between 2 regions that are homologous with human chromosome 6p and chromosome 5. Taketo et al. (1994) stated that preliminary Southern analysis of DNA samples from a panel of mouse/human somatic cell hybrids showed concordant hybridization of the MAK gene and the ROS1 gene, previously mapped to 6q22.


Molecular Genetics

In a patient of Jewish ancestry with retinitis pigmentosa (RP62; 614181), Tucker et al. (2011) performed exome sequencing and identified homozygosity for 353-bp insertion of an Alu repeat in exon 9 of the MAK gene (154235.0001). Screening of 1,798 unrelated individuals with autosomal recessive RP identified 20 additional probands, also of Jewish ancestry, who were homozygous for the same Alu insertion. Studies in skin-derived induced pluripotent stem cells expressing retinal differentiation markers demonstrated that the Alu insertion disrupts correct splicing of exon 9, which also results in loss of the retina-specific exon 12, thereby preventing mature retinal cells from expressing the correct MAK isoform.

By whole-exome sequencing in a 31-year-old Turkish woman with RP who was negative for mutation in known RP genes, Ozgul et al. (2011) identified homozygosity for a nonsense mutation in the MAK gene (154235.0002) that segregated with disease in the family. Whole-genome SNP analysis in 334 isolated or autosomal recessive RP patients of Dutch, Italian, Israeli, and Palestinian origin revealed 11 probands with a large homozygous region encompassing the MAK gene; homozygous missense mutations in MAK were identified in 3 of the probands (154235.0003-154235.0005).


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 RETINITIS PIGMENTOSA 62

MAK, 353-BP ALU INS, EX9
   RCV000022647

In a patient of Jewish ancestry with retinitis pigmentosa (RP62; 614181), Tucker et al. (2011) identified homozygosity for insertion of a 353-bp Alu repeat in exon 9 of the MAK gene between codons 428 and 429, predicted to result in the insertion of 31 incorrect amino acids followed by premature termination. Screening of 1,798 unrelated individuals with autosomal recessive RP identified 20 additional probands who were homozygous for the same Alu insertion; 2 affected relatives in 2 of the families were also found to be homozygous for the Alu insertion. None of the 5 unaffected relatives who were available for study were homozygous for the insertion, and the mutation was not detected in 2,952 unrelated individuals without eye disease. All 21 families with the Alu insertion reported Jewish ancestry, although there was no known consanguinity. In 1 family, the unaffected mother had emigrated from Turkey, whereas the unaffected father had emigrated from Russia, suggesting that the founder of the mutation may have lived before the separation of the Sephardic and Ashkenazi groups in the Middle Ages. Analysis of skin-derived induced pluripotent stem cells expressing retinal differentiation markers demonstrated that the Alu insertion disrupts correct splicing of exon 9, which also results in loss of the retina-specific exon 12, thereby preventing mature retinal cells from expressing the correct MAK isoform.


.0002 RETINITIS PIGMENTOSA 62

MAK, GLY240TER
  
RCV000022648

In a 31-year-old Turkish woman with retinitis pigmentosa (RP62; 614181) who was negative for mutation in known RP genes, Ozgul et al. (2011) identified homozygosity for a 718C-T transition in the MAK gene, resulting in a gln240-to-ter (Q240X) substitution within the conserved kinase domain that was predicted to remove kinase subdomain XI. Her unaffected first-cousin parents and 4 unaffected sibs were heterozygous for the mutation, which was not found in 130 Turkish controls.


.0003 RETINITIS PIGMENTOSA 62

MAK, ASN130HIS
  
RCV000022649

In a 57-year-old Dutch woman with retinitis pigmentosa (RP62; 614181), Ozgul et al. (2011) identified homozygosity for a 388A-C transversion in the MAK gene, resulting in an asn130-to-his (N130H) substitution at a highly conserved residue within the kinase domain. The mutation was not found in 163 Dutch controls. In vitro kinase analysis demonstrated that the N130H mutation resulted in complete loss of kinase activity compared to wildtype.


.0004 RETINITIS PIGMENTOSA 62

MAK, GLY13SER
  
RCV000022650...

In a 23-year-old Dutch man with severe tunnel vision due to retinitis pigmentosa (RP62; 614181), Ozgul et al. (2011) identified homozygosity for a 37G-A transition in the MAK gene, resulting in a gly13-to-ser (G13S) substitution at a highly conserved residue within the kinase domain. The mutation was not found in 163 Dutch controls. In vitro kinase analysis demonstrated that the G13S mutation resulted in complete loss of kinase activity compared to wildtype.


.0005 RETINITIS PIGMENTOSA 62

MAK, ARG166HIS
  
RCV000022651...

In 3 Israeli sibs of Oriental Jewish origin with retinitis pigmentosa (RP62; 614181), Ozgul et al. (2011) identified homozygosity for a 497G-A transition in the MAK gene, resulting in an arg166-to-his (R166H) substitution at a highly conserved residue within the kinase domain. One unaffected sib was heterozygous for the mutation, whereas 2 additional unaffected sibs did not carry R166H; the mutation was detected in 1 of 217 Oriental Jewish controls.


REFERENCES

  1. Matsushime, H., Jinno, A., Takagi, N., Shibuya, M. A novel mammalian protein kinase gene (mak) is highly expressed in testicular germ cells at and after meiosis. Molec. Cell. Biol. 10: 2261-2268, 1990. [PubMed: 2183027, related citations] [Full Text]

  2. Omori, Y., Chaya, T., Katoh, K., Kajimura, N., Sato, S., Muraoka, K., Ueno, S., Koyasu, T., Kondo, M., Furukawa, T. Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival. Proc. Nat. Acad. Sci. 107: 22671-22676, 2010. [PubMed: 21148103, images, related citations] [Full Text]

  3. Ozgul, R. K., Siemiatkowska, A. M., Yucel, D., Myers, C. A., Collin, R. W. J., Zonneveld, M. N., Beryozkin, A., Banin, E., Hoyng, C. B., van den Born, L. I., The European Retinal Disease Consortium, Bose, R., Shen, W., Sharon, D., Cremers, F. P. M., Klevering, B. J., den Hollander, A. I., Corbo, J. C. Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa. Am. J. Hum. Genet. 89: 253-264, 2011. [PubMed: 21835304, images, related citations] [Full Text]

  4. Taketo, M., Jinno, A., Yamaguchi, S., Matushime, H., Shibuya, M., Seldin, M. F. Mouse Mak gene for male germ cell-associated kinase maps to chromosome 13. Genomics 19: 397-398, 1994. [PubMed: 8188277, related citations] [Full Text]

  5. Tucker, B. A., Scheetz, T. E., Mullins, R. F., DeLuca, A. P., Hoffmann, J. M., Johnston, R. M., Jacobson, S. G., Sheffield, V. C., Stone, E. M. Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa. Proc. Nat. Acad. Sci. 108: E569-E576, 2011. [PubMed: 21825139, images, related citations] [Full Text]


Marla J. F. O'Neill - updated : 9/12/2011
Marla J. F. O'Neill - updated : 8/19/2011
Creation Date:
Victor A. McKusick : 2/18/1994
carol : 08/06/2019
alopez : 10/24/2011
carol : 9/13/2011
terry : 9/12/2011
terry : 9/12/2011
wwang : 8/22/2011
terry : 8/19/2011
mimadm : 4/14/1994
carol : 2/18/1994

* 154235

MALE GERM CELL-ASSOCIATED KINASE; MAK


HGNC Approved Gene Symbol: MAK

Cytogenetic location: 6p24.2     Genomic coordinates (GRCh38): 6:10,762,723-10,838,539 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
6p24.2 Retinitis pigmentosa 62 614181 Autosomal recessive 3

TEXT

Cloning and Expression

Male germ cell-associated kinase is one of the protein kinases that was isolated by weak cross-hybridization with the v-ros (165020) protein kinase sequence (Matsushime et al., 1990). The gene encoding this kinase is expressed almost exclusively in testis, mainly in germ cells at and/or after the pachytene stage, as 66- and 60-kD proteins that form a distinct complex with cellular phosphoprotein p210. The p210 protein is sufficiently phosphorylated in vitro by the MAK gene product at serine and threonine residues. These results suggest that the MAK gene plays an important role in spermatogenesis.

Using mono- and polyclonal antibodies, Tucker et al. (2011) localized MAK to human retina. In photoreceptor cells, labeling was predominantly observed in the outer nuclear layer, axons, and inner segments. Outer segments that contained abundant rhodopsin (180380) did not show strong MAK expression, which was generally not observed distal to the connecting cilium. The localization of MAK to photoreceptor cells was also observed in the foveal cones, in which inner segments as well as the Henle fiber layer of axons were strongly positive. By Northern blot analysis of normal human retina, Tucker et al. (2011) detected the largest and most abundant MAK transcript to be slightly larger than 2,000 nucleotides in length; RT-PCR analysis followed by DNA sequencing revealed a novel 75-bp exon not previously known to exist in humans, located between exons 11 and 12 of the longest previously published human MAK transcript. This 14-exon retinal transcript, in which the newly recognized exon was designated to be exon 12, contains 648 amino acids with a calculated molecular mass of 73.3 kD. RT-PCR analysis of human tissues showed that exon 12-containing MAK transcript is only expressed in retina.

Ozgul et al. (2011) performed PCR amplification of full-length MAK coding sequence from human retina and identified a photoreceptor-enriched alternative exon (exon 13), previously reported in mice (Omori et al., 2010), that corresponded to a 25-residue block of phylogenetic conservation. Expression analysis revealed that the longer isoform, including the alternative exon, is the predominant species in the retina, with barely detectable expression of the shorter isoform. In testis, the shorter isoform predominates, whereas the longer form is detectable at lower levels.


Gene Structure

Tucker et al. (2011) determined that the MAK gene contains 14 exons.


Mapping

Using a panel of DNA samples from an interspecific cross, Taketo et al. (1994) mapped the Mak gene to mouse chromosome 13 in an area situated between 2 regions that are homologous with human chromosome 6p and chromosome 5. Taketo et al. (1994) stated that preliminary Southern analysis of DNA samples from a panel of mouse/human somatic cell hybrids showed concordant hybridization of the MAK gene and the ROS1 gene, previously mapped to 6q22.


Molecular Genetics

In a patient of Jewish ancestry with retinitis pigmentosa (RP62; 614181), Tucker et al. (2011) performed exome sequencing and identified homozygosity for 353-bp insertion of an Alu repeat in exon 9 of the MAK gene (154235.0001). Screening of 1,798 unrelated individuals with autosomal recessive RP identified 20 additional probands, also of Jewish ancestry, who were homozygous for the same Alu insertion. Studies in skin-derived induced pluripotent stem cells expressing retinal differentiation markers demonstrated that the Alu insertion disrupts correct splicing of exon 9, which also results in loss of the retina-specific exon 12, thereby preventing mature retinal cells from expressing the correct MAK isoform.

By whole-exome sequencing in a 31-year-old Turkish woman with RP who was negative for mutation in known RP genes, Ozgul et al. (2011) identified homozygosity for a nonsense mutation in the MAK gene (154235.0002) that segregated with disease in the family. Whole-genome SNP analysis in 334 isolated or autosomal recessive RP patients of Dutch, Italian, Israeli, and Palestinian origin revealed 11 probands with a large homozygous region encompassing the MAK gene; homozygous missense mutations in MAK were identified in 3 of the probands (154235.0003-154235.0005).


ALLELIC VARIANTS 5 Selected Examples):

.0001   RETINITIS PIGMENTOSA 62

MAK, 353-BP ALU INS, EX9
ClinVar: RCV000022647

In a patient of Jewish ancestry with retinitis pigmentosa (RP62; 614181), Tucker et al. (2011) identified homozygosity for insertion of a 353-bp Alu repeat in exon 9 of the MAK gene between codons 428 and 429, predicted to result in the insertion of 31 incorrect amino acids followed by premature termination. Screening of 1,798 unrelated individuals with autosomal recessive RP identified 20 additional probands who were homozygous for the same Alu insertion; 2 affected relatives in 2 of the families were also found to be homozygous for the Alu insertion. None of the 5 unaffected relatives who were available for study were homozygous for the insertion, and the mutation was not detected in 2,952 unrelated individuals without eye disease. All 21 families with the Alu insertion reported Jewish ancestry, although there was no known consanguinity. In 1 family, the unaffected mother had emigrated from Turkey, whereas the unaffected father had emigrated from Russia, suggesting that the founder of the mutation may have lived before the separation of the Sephardic and Ashkenazi groups in the Middle Ages. Analysis of skin-derived induced pluripotent stem cells expressing retinal differentiation markers demonstrated that the Alu insertion disrupts correct splicing of exon 9, which also results in loss of the retina-specific exon 12, thereby preventing mature retinal cells from expressing the correct MAK isoform.


.0002   RETINITIS PIGMENTOSA 62

MAK, GLY240TER
SNP: rs779514800, ClinVar: RCV000022648

In a 31-year-old Turkish woman with retinitis pigmentosa (RP62; 614181) who was negative for mutation in known RP genes, Ozgul et al. (2011) identified homozygosity for a 718C-T transition in the MAK gene, resulting in a gln240-to-ter (Q240X) substitution within the conserved kinase domain that was predicted to remove kinase subdomain XI. Her unaffected first-cousin parents and 4 unaffected sibs were heterozygous for the mutation, which was not found in 130 Turkish controls.


.0003   RETINITIS PIGMENTOSA 62

MAK, ASN130HIS
SNP: rs387906646, ClinVar: RCV000022649

In a 57-year-old Dutch woman with retinitis pigmentosa (RP62; 614181), Ozgul et al. (2011) identified homozygosity for a 388A-C transversion in the MAK gene, resulting in an asn130-to-his (N130H) substitution at a highly conserved residue within the kinase domain. The mutation was not found in 163 Dutch controls. In vitro kinase analysis demonstrated that the N130H mutation resulted in complete loss of kinase activity compared to wildtype.


.0004   RETINITIS PIGMENTOSA 62

MAK, GLY13SER
SNP: rs387906647, gnomAD: rs387906647, ClinVar: RCV000022650, RCV001851998

In a 23-year-old Dutch man with severe tunnel vision due to retinitis pigmentosa (RP62; 614181), Ozgul et al. (2011) identified homozygosity for a 37G-A transition in the MAK gene, resulting in a gly13-to-ser (G13S) substitution at a highly conserved residue within the kinase domain. The mutation was not found in 163 Dutch controls. In vitro kinase analysis demonstrated that the G13S mutation resulted in complete loss of kinase activity compared to wildtype.


.0005   RETINITIS PIGMENTOSA 62

MAK, ARG166HIS
SNP: rs387906648, ClinVar: RCV000022651, RCV001003075, RCV001388421

In 3 Israeli sibs of Oriental Jewish origin with retinitis pigmentosa (RP62; 614181), Ozgul et al. (2011) identified homozygosity for a 497G-A transition in the MAK gene, resulting in an arg166-to-his (R166H) substitution at a highly conserved residue within the kinase domain. One unaffected sib was heterozygous for the mutation, whereas 2 additional unaffected sibs did not carry R166H; the mutation was detected in 1 of 217 Oriental Jewish controls.


REFERENCES

  1. Matsushime, H., Jinno, A., Takagi, N., Shibuya, M. A novel mammalian protein kinase gene (mak) is highly expressed in testicular germ cells at and after meiosis. Molec. Cell. Biol. 10: 2261-2268, 1990. [PubMed: 2183027] [Full Text: https://doi.org/10.1128/mcb.10.5.2261-2268.1990]

  2. Omori, Y., Chaya, T., Katoh, K., Kajimura, N., Sato, S., Muraoka, K., Ueno, S., Koyasu, T., Kondo, M., Furukawa, T. Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival. Proc. Nat. Acad. Sci. 107: 22671-22676, 2010. [PubMed: 21148103] [Full Text: https://doi.org/10.1073/pnas.1009437108]

  3. Ozgul, R. K., Siemiatkowska, A. M., Yucel, D., Myers, C. A., Collin, R. W. J., Zonneveld, M. N., Beryozkin, A., Banin, E., Hoyng, C. B., van den Born, L. I., The European Retinal Disease Consortium, Bose, R., Shen, W., Sharon, D., Cremers, F. P. M., Klevering, B. J., den Hollander, A. I., Corbo, J. C. Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa. Am. J. Hum. Genet. 89: 253-264, 2011. [PubMed: 21835304] [Full Text: https://doi.org/10.1016/j.ajhg.2011.07.005]

  4. Taketo, M., Jinno, A., Yamaguchi, S., Matushime, H., Shibuya, M., Seldin, M. F. Mouse Mak gene for male germ cell-associated kinase maps to chromosome 13. Genomics 19: 397-398, 1994. [PubMed: 8188277] [Full Text: https://doi.org/10.1006/geno.1994.1082]

  5. Tucker, B. A., Scheetz, T. E., Mullins, R. F., DeLuca, A. P., Hoffmann, J. M., Johnston, R. M., Jacobson, S. G., Sheffield, V. C., Stone, E. M. Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa. Proc. Nat. Acad. Sci. 108: E569-E576, 2011. [PubMed: 21825139] [Full Text: https://doi.org/10.1073/pnas.1108918108]


Contributors:
Marla J. F. O'Neill - updated : 9/12/2011
Marla J. F. O'Neill - updated : 8/19/2011

Creation Date:
Victor A. McKusick : 2/18/1994

Edit History:
carol : 08/06/2019
alopez : 10/24/2011
carol : 9/13/2011
terry : 9/12/2011
terry : 9/12/2011
wwang : 8/22/2011
terry : 8/19/2011
mimadm : 4/14/1994
carol : 2/18/1994