HGNC Approved Gene Symbol: FRMD7
Cytogenetic location: Xq26.2 Genomic coordinates (GRCh38) : X:132,076,990-132,128,020 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26.2 | Nystagmus 1, congenital, X-linked | 310700 | X-linked | 3 |
| Nystagmus, infantile periodic alternating, X-linked | 310700 | X-linked | 3 |
Tarpey et al. (2006) identified the FRMD7 gene within the critical interval for X-linked congenital nystagmus (NYS1; 310700) on Xq26-q27. The 714-amino acid FRMD7 protein shares close homology with FARP1 (602654) and FARP2 (617586) that is concentrated at the N terminus of the protein, where B41 and FERM-C domains are present. Expression analysis of FRMD7 showed that the mRNA is present in most tissues at low levels. Tarpey et al. (2006) confirmed this by RT-PCR, detecting expression in human adult kidney, liver, pancreas, and, at low levels, heart and brain. In human fetal tissue, they detected the transcript only in kidney. In situ hybridization experiments in human embryonic brain showed expression in the ventricular layer of the forebrain, midbrain, cerebellum primordium, spinal cord, and developing neural retina in embryos approximately 56 days postovulation. In earlier embryos the expression was restricted to the mid- and hindbrain, regions known to be involved in motor control of eye movement.
The FRMD7 gene comprises 12 exons (Tarpey et al., 2006).
The FRMD7 gene maps to chromosome Xq26.2 (Tarpey et al., 2006).
Using in situ hybridization and immunohistochemistry, Betts-Henderson et al. (2010) showed that FRMD7 expression was spatially and temporally regulated in both the human and mouse brain during embryonic and fetal development. Frmd7 expression was upregulated upon retinoic acid (RA)-induced differentiation of mouse neuroblastoma NEURO2A cells, suggesting FRMD7 may play a role in this process. Knockdown of Frmd7 during neuronal differentiation resulted in altered neurite development. Betts-Henderson et al. (2010) suggested that FRMD7 may be involved in multiple aspects of neuronal development.
By in situ hybridization studies of human brain during mid-to-late embryonic stages, Thomas et al. (2011) found FRMD7 expression in neuronal tissue in structures involved with the vestibuloocular reflex and optokinetic reflex. Staining was found in the afferent arms of the vestibuloocular reflex consisting of the otic vesicle, cranial nerve VIII, and vestibular ganglia. Expression was also found within the afferent arm of the optokinetic reflex in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the vestibular nuclei.
Tarpey et al. (2006) screened 16 families with X-linked congenital nystagmus (NYS1; 310700) using 17 markers extending from Xq26 to Xq27. In all 16 families, marker haplotypes were compatible with linkage to Xq26-q27. Recombinant events in affected males in 1 family refined the location of NYS1 to an interval of approximately 7.5 Mb between markers DXS1047 and DXS1041. The candidate interval contained more than 80 genes. Tarpey et al. (2006) performed high-throughput DNA sequence analysis of all coding exons of all genes within this interval in 1 affected male from each of the 16 linked families. In 15 of the 16 families, mutations were detected in the FRMD7 gene. Screening of 14 families with 2 or more affected individuals identified mutations in 8 (57%). Screening of 42 singleton cases of idiopathic congenital nystagmus (28 males, 14 females) yielded 3 mutations (7%). The homologous protein FARP2 modulates the length and the degree of branching of neurites in rat embryonic cortical neurons and reorganizes the cytoskeleton. As a plausible explanation of how defects in the FRMD7 protein cause nystagmus, Tarpey et al. (2006) hypothesized that null mutations in FRMD7 alter neurite length and degree of branching of neurons as they develop in the midbrain, cerebellum, and retina.
In affected members of families with NYS1, Zhang et al. (2007), Shiels et al. (2007), and Kaplan et al. (2008) identified different mutations in the FRMD7 gene (300628.0006-300628.0008). The families were of Chinese, Caucasian, and Turkish origin, respectively.
In affected members of 6 unrelated Chinese families with X-linked congenital nystagmus, He et al. (2008) identified a truncating mutation in the FRMD7 gene (1274delTG; 300628.0009). Haplotype analysis indicated a founder effect. The phenotype was characterized by onset in infancy of horizontal pendular oscillations of both eyes and varying degrees of decreased visual acuity. Some patients had astigmatism. None had abnormal appearance of the fundus or color vision defects. In a review of the literature, He et al. (2008) concluded that FRMD7 mutations account for about 47% of X-linked nystagmus in Chinese patients with the disorder.
Thomas et al. (2011) identified FRMD7 mutations (see, e.g., 300628.0002, 300628.0005, 300628.0010-300628.0011) in 26 patients from 10 families in which at least 1 individual had X-linked infantile periodic alternating nystagmus (XIPAN; see 310700), as well as in 1 singleton patient with the disorder. PAN was not diagnosed clinically in any of the individuals, but was apparent in some mutation carriers after eye movement recordings during prolonged fixation. Several families showed phenotypic heterogeneity, with only some having PAN on eye movement recordings; all had clinical nystagmus. Most patients had good visual acuity, but none with PAN had a horizontal optokinetic reflex. Based on immunohistochemical expression studies in human embryonic brain and phenotypic data, Thomas et al. (2011) hypothesized that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems.
In a family of Italian/German extraction with X-linked congenital nystagmus (310700), Tarpey et al. (2006) found a truncating mutation of the FRMD7 gene: 601C-T, gln201 to stop (Q201X). The predicted truncated protein contained 28% of the wildtype protein.
In a family derived from England and India, Tarpey et al. (2006) found that X-linked congenital nystagmus (310700) was associated with a nonsense mutation in the FRMD7 gene: 1003C-T, arg335 to stop (R335X). The truncated protein was predicted to contain 47% of wildtype.
Thomas et al. (2011) identified the R335X mutation in 4 males from 2 unrelated families with X-linked periodic alternating nystagmus (PAN) (see 310700). Of note, the diagnosis was not made clinically, but only after the use of eye movement recordings during prolonged duration of fixation. Most patients had good visual acuity, but none had a horizontal optokinetic reflex.
Four of 5 splice site mutations found by Tarpey et al. (2006) in cases of X-linked congenital nystagmus (310700) were at conserved splice donor residues (position +1 and position +2) and were predicted to be pathologic by classic exon skipping and nonsense-mediated decay. One of these truncating mutations, IVS3+2T-G, was found in a family in England.
In a family originating in England, Tarpey et al. (2006) found that X-linked congenital nystagmus (310700) was associated with a silent variant of the FRMD7 gene, 252G-A (val84 to val), which created a new splice acceptor site within exon 4 that resulted in the loss of a transcript containing the sequence of exons 1 through 5 and the rare presence of a transcript with exon 4 skipped in lymphocytes.
In a family from Ireland, Tarpey et al. (2006) found that X-linked congenital nystagmus (310700) was associated with a missense mutation of the FRMD7 gene: 70G-A, gly24 to arg (G24R).
Thomas et al. (2011) identified the G24R mutation in affected members of a large family with X-linked nystagmus reported by Hertle et al. (2005). All patients had clinical nystagmus, and all 4 who had eye movement recordings showed periodic alternating nystagmus (PAN) (see 310700). The mutation was predicted to result in an unstable protein. Most patients had good visual acuity, but none with PAN had a horizontal optokinetic reflex. The mutation occurs in the FERM-N domain.
In affected members of a large Chinese family with X-linked congenital nystagmus (310700) reported by Guo et al. (2006), Zhang et al. (2007) identified an in-frame 3-bp deletion (41delAGA) in exon 1 of the FRMD7 gene, resulting in the deletion of residue lys14. The mutation was not found in 196 normal controls. Obligate female carriers were not affected. Zhang et al. (2007) noted that inheritance in the Chinese family was consistent with X-linked recessive, but that this mutation had been identified by Tarpey et al. (2006) in an English family with X-linked dominant inheritance. Skewed X inactivation was offered as an explanation.
In affected members of 2 unrelated Caucasian families with X-linked infantile nystagmus (310700), Shiels et al. (2007) identified a 425T-G transversion in exon 6 of the FRMD7 gene, resulting in a leu142-to-arg (L142R) substitution. Haplotype analysis confirmed that the 2 families were not related. This mutation had also been identified in an Irish family by Tarpey et al. (2006).
In affected members of a large Turkish family with X-linked congenital nystagmus (310700), Kaplan et al. (2008) identified a 686C-G transversion in exon 8 of the FRMD7 gene, resulting in an arg229-to-gly (R229G) substitution. There were at least 7 affected females, and molecular studies showed that some had markedly skewed X-chromosome inactivation.
In affected members of 6 unrelated Chinese families with X-linked congenital nystagmus (310700), He et al. (2008) identified a 2-bp deletion (1274delTG) in exon 12 of the FRMD7 gene, resulting in a frameshift and premature termination. The mutation was not identified in 400 male controls. Haplotype analysis indicated a founder effect. The phenotype was characterized by onset in infancy of horizontal pendular oscillations of both eyes and varying degrees of decreased visual acuity. Some patients had astigmatism. None had abnormal appearance of the fundus or color vision defects.
In affected members of a 5-generation family with X-linked congenital nystagmus (301700), Thomas et al. (2011) identified a 691T-G transversion in the FRMD7 gene, resulting in a leu231-to-val (L231V) substitution in the FERM-C domain and predicted to result in protein instability. All affected individuals had clinical nystagmus, and 4 of 5 who had eye movement recordings showed periodic alternating nystagmus (PAN) (see 301700). Most patients had good visual acuity, but none with PAN had a horizontal optokinetic reflex.
In affected members of a 3-generation family with X-linked congenital nystagmus (301700), Thomas et al. (2011) identified an 812G-A transition in the FRMD7 gene, resulting in a cys271-to-tyr (C271Y) substitution in the FERM-C domain and predicted to result in protein instability. All affected individuals had clinical nystagmus, and 3 of 5 who had eye movement recordings showed periodic alternating nystagmus (PAN) (see 301700). Most patients had good visual acuity, but none with PAN had a horizontal optokinetic reflex.
In 2 brothers with X-linked infantile nystagmus (310700) from a 3-generation family, Khan et al. (2011) detected a hemizygous splice variant in intron 11 of the FRMD7 gene (1050+5G-A). In silico analysis predicted that this variant would affect the splice donor site, resulting in a 345-base inclusion of intron 11, a resultant frameshift, and a truncated protein of 372 amino acids. The affected brothers had infantile nystagmus with no evidence of associated visual or neurologic disease. The mutation was also found in 3 asymptomatic female members: a sister, the mother, and the maternal grandmother. All 3 of these had delayed corrective saccades (prolonged pursuit) during optokinetic nystagmus (OKN) drum testing. A brother and the father, who were asymptomatic and did not carry the mutation, had unremarkable examination findings. A symptomatic maternal aunt had infantile nystagmus in addition to congenital fibrosis of the extraocular muscles (CFEOM; see 135700). Sequencing and allele sharing analysis excluded the FRMD7 mutation in this individual, and her phenotype was also not related to mutation in known CFEOM genes; Khan et al. (2011) concluded that nystagmus in this individual represented a distinct disorder. Khan et al. (2011) concluded that prolonged pursuit responses during OKN drum testing in asymptomatic female carriers was consistent with the concept that infantile nystagmus was an abnormally increased pursuit oscillation.
Betts-Henderson, J., Bartesaghi, S., Crosier, M., Lindsay, S., Chen, H.-L., Salomoni, P., Gottlob, I., Nicotera, P. The nystagmus-associated FRMD7 gene regulates neuronal outgrowth and development. Hum. Molec. Genet. 19: 342-351, 2010. [PubMed: 19892780] [Full Text: https://doi.org/10.1093/hmg/ddp500]
Guo, X., Li, S., Jia, X., Xiao, X., Wang, P., Zhang, Q. Linkage analysis of two families with X-linked recessive congenital motor nystagmus. J. Hum. Genet. 51: 76-80, 2006. [PubMed: 16240070] [Full Text: https://doi.org/10.1007/s10038-005-0316-y]
He, X., Gu, F., Wang, Z., Wang, C., Tong, Y., Wang, Y., Yang, J., Liu, W., Zhang, M., Ma, X. A novel frameshift mutation in FRMD7 causing X-linked idiopathic congenital nystagmus. Genet. Test 12: 607-613, 2008. [PubMed: 19072571] [Full Text: https://doi.org/10.1089/gte.2008.0070]
Hertle, R. W., Yang, D., Kelly, K., Hill, V. M., Atkin, J., Seward, A. X-linked infantile periodic alternating nystagmus. Ophthal. Genet. 26: 77-84, 2005. [PubMed: 16020310] [Full Text: https://doi.org/10.1080/13816810590968014]
Kaplan, Y., Vargel, I., Kansu, T., Akin, B., Rohmann, E., Kamaci, S., Uz, E., Ozcelik, T., Wollnik, B., Akarsu, N. A. Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene. Brit. J. Ophthal. 92: 135-141, 2008. [PubMed: 17962394] [Full Text: https://doi.org/10.1136/bjo.2007.128157]
Khan, A. O., Shinwari, J., Al-Sharif, L., Khalil, D. S., Al Tassan, N. Prolonged pursuit by optokinetic drum testing in asymptomatic female carriers of novel FRMD7 splice mutation c.1050+5G-A. Arch. Ophthal. 129: 936-940, 2011. Note: Erratum: Arch. Ophthal. 129: 1217 only, 2011. [PubMed: 21746984] [Full Text: https://doi.org/10.1001/archophthalmol.2011.166]
Shiels, A., Bennett, T. M., Prince, J. B., Tychsen, L. X-linked idiopathic infantile nystagmus associated with a missense mutation in FRMD7. Molec. Vis. 13: 2233-2241, 2007. [PubMed: 18087240]
Tarpey, P., Thomas, S., Sarvananthan, N., Mallya, U., Lisgo, S., Talbot, C. J., Roberts, E. O., Awan, M., Surendran, M., McLean, R. J., Reinecke, R. D., Langmann, A., and 30 others. Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nature Genet. 38: 1242-1244, 2006. Note: Erratum: Nature Genet. 43: 720 only, 2011. [PubMed: 17013395] [Full Text: https://doi.org/10.1038/ng1893]
Thomas, M. G., Crosier, M., Lindsay, S., Kumar, A., Thomas, S., Araki, M., Talbot, C. J., McLean, R. J., Surendran, M., Taylor, K., Leroy, B. P., Moore, A. T., Hunter, D. G., Hertle, R. W., Tarpey, P., Langmann, A., Lindner, S., Brandner, M., Gottlob, I. The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus. Brain 134: 892-902, 2011. [PubMed: 21303855] [Full Text: https://doi.org/10.1093/brain/awq373]
Zhang, Q., Xiao, X., Li, S., Guo, X. FRMD7 mutations in Chinese families with X-linked congenital motor nystagmus. Molec. Vis. 13: 1375-1378, 2007. [PubMed: 17768376]