Alternative titles; symbols
SNOMEDCT: 717787005; ORPHA: 2196; DO: 0060881;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.2 | Hypomagnesemia 5, renal, with ocular involvement | 248190 | Autosomal recessive | 3 | CLDN19 | 610036 |
A number sign (#) is used with this entry because of evidence that renal hypomagnesemia-5 with ocular involvement (HOMG5) is caused by homozygous or compound heterozygous mutation in the claudin-19 gene (CLDN19; 610036) on chromosome 3q28.
HOMG5 is an autosomal recessive disorder characterized by severe renal magnesium wasting, progressive renal failure, nephrocalcinosis, and severe visual impairment (Konrad et al., 2006). Amelogenesis imperfecta may also be present in some patients (Yamaguti et al., 2017).
For a discussion of genetic heterogeneity of renal hypomagnesemia, see 602014.
In the son and daughter of consanguineous parents, Meier et al. (1979) described nephrocalcinosis with idiopathic hypercalciuria dating from the first years of life and bilateral chorioretinal 'scars' in the macula interpreted as colobomata. Nystagmus and malignant myopia were present. Both children had inguinal hernias.
Konrad et al. (2006) clinically characterized 1 Swiss and 8 Spanish/Hispanic families affected with severe hypomagnesemia due to renal wasting, nephrocalcinosis, and progressive renal failure. The Swiss patient had been described by Meier et al. (1979), and 4 of the Hispanic patients by Rodriguez-Soriano and Vallo (1994). Despite similarities to patients with HOMG3 (248250), in whom mutations in the CLDN16 gene (603959) had been identified, no CLDN16 mutations were found in these cases. Affected individuals in these families also had severe visual impairment, characterized by macular colobomata, significant myopia, and horizontal nystagmus.
Yamaguti et al. (2017) characterized the enamel phenotype of 9 patients from 6 unrelated families with HOMG5, including 3 Brazilian families (families 1, 2, and 3), and 3 French families (families 4, 5, and 6) that were previously studied by Godron et al. (2012) (patients 16, 15, and 11.1, respectively). All 9 patients exhibited amelogenesis imperfecta with varying degrees of severity, even among individual teeth within the same patient. Dental features included yellow-brownish discoloration consistent with hypomature enamel, linear and diffuse opacities, hypoplastic enamel with pits and grooves, and generalized reduction in enamel thickness as well as areas of total enamel absence. Some patients also showed microfractures and tooth wear. In addition, the authors noted normal vision in 3 of the Brazilian patients, including the proband from family 1 and 2 of 3 affected sibs from family 2, and suggested that ocular defects are incompletely penetrant in HOMG5.
The transmission pattern of HOMG5 in the families reported by Konrad et al. (2006) was consistent with autosomal recessive inheritance.
Konrad et al. (2006) demonstrated 2 different homozygous missense mutations in the CLDN19 gene in families with renal magnesium wasting, renal failure, and severe ocular involvement. In 7 of 8 Spanish/Hispanic families they found a gly20-to-asp substitution (G20D; 610036.0001) in the first transmembrane domain of claudin-19. In the Swiss family they detected a gln57-to-glu substitution (Q57E; 610036.0002) in the first extracellular loop. They subsequently identified a consanguineous Turkish family and found a homozygous leu90-to-pro substitution (L90P; 610036.0003) in the 2 affected children. Haplotype analysis indicated that G20D was a founder mutation.
Godron et al. (2012) identified homozygous or compound heterozygous mutations in affected members of 18 families with HOMG5, including 15 members from 14 families of French or Spanish descent with the G20D founder mutation (see, e.g., 610036.0001 and 610036.0005).
In 6 patients from 3 unrelated Brazilian families with HOMG and amelogenesis imperfecta, Yamaguti et al. (2017) identified homozygous or compound heterozygous mutations in the CLDN19 gene (see, e.g., 610036.0001 and 610036.0004).
Godron et al. (2012) retrospectively reviewed 32 patients from 26 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis due to CLDN16 or CLDN19 mutations. Ocular abnormalities were found only in patients with CLDN19 mutations, who also displayed more severe renal impairment than patients with CLDN16 mutations. The risk of end-stage renal disease in patients with CLDN19 mutations was twice that in patients with CLDN16 mutations.
Godron, A., Harambat, J., Boccio, V., Mensire, A., May, A., Rigothier, C., Couzi, L., Barrou, B., Godin, M., Chauveau, D., Faguer, S., Vallet, M., Cochat, P., Eckart, P., Guest, G., Guigonis, V., Houillier, P., Blanchard, A., Jeunemaitre, X., Vargas-Poussou, R. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clin. J. Am. Soc. Nephrol. 7: 801-809, 2012. [PubMed: 22422540] [Full Text: https://doi.org/10.2215/CJN.12841211]
Konrad, M., Schaller, A., Seelow, D., Pandey, A. V., Waldegger, S., Lesslauer, A., Vitzthum, H., Suzuki, Y., Luk, J. M., Becker, C., Schlingmann, K. P., Schmid, M., and 11 others. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am. J. Hum. Genet. 79: 949-957, 2006. [PubMed: 17033971] [Full Text: https://doi.org/10.1086/508617]
Meier, W., Blumberg, A., Imahorn, W., De Luca, F., Wildberger, H., Oetliker, O. Idiopathic hypercalciuria with bilateral macular colobomata: a new variant of oculo-renal syndrome. Helv. Paediat. Acta 34: 257-269, 1979. [PubMed: 500385]
Rodriguez-Soriano, J., Vallo, A. Pathophysiology of the renal acidification defect present in the syndrome of familial hypomagnesaemia-hypercalciuria. Pediat. Nephrol. 8: 431-435, 1994. [PubMed: 7947033] [Full Text: https://doi.org/10.1007/BF00856522]
Yamaguti, P. M., Neves, F. A. R., Hotton, D., Bardet, C., de La Dure-Molla, M., Castro, L. C., Scher, M. C., Barbosa, M. E., Ditsch, C., Fricain, J.-C., de La Faille, R., Figueres, M.-L., Vargas-Poussou, R., Houillier, P., Chaussain, C., Babajko, S., Berdal, A., Acevedo, A. C. Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations. J. Med. Genet. 54: 26-37, 2017. Note: Erratum: J. Med. Genet. 54: 786 only, 1017. [PubMed: 27530400] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103956]