Retinitis Pigmentosa 28
A number sign (#) is used with this entry because retinitis pigmentosa-28 (RP28) is caused by homozygous or compound heterozygous mutation in the FAM161A gene (613596) on chromosome 2p15.
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical FeaturesGu et al. (1999) described a consanguineous Indian family in which 4 members in 2 generations had autosomal recessive RP. Age of onset was between 5 and 15 years. The 3 oldest members, aged 39 to 47, had severe visual handicap.
Langmann et al. (2010) studied 3 German patients with RP28 and reviewed the phenotype of the Indian family studied by Gu et al. (1999), stating that this type of retinal dystrophy shows no unique clinical features. The course of the disease is rather slow, with age of onset in the second or third decade, severe visual handicap in the fifth decade, and legal blindness in the sixth to seventh decades. However, the youngest Indian patient had early onset of disease, at 5 years of age, and more rapid progression, with a visual acuity at age 15 of 3/60 in the left eye and the right eye reduced to counting fingers. Langmann et al. (2010) concluded that RP28 represents a variable phenotype in terms of disease onset and progression, which could be due to genetic or environmental modifiers.
Bandah-Rozenfeld et al. (2010) studied 20 families from Israel and the Palestinian territories with RP28, noting that clinical manifestations varied but were largely within the spectrum associated with autosomal recessive RP. On funduscopy, pallor of the optic discs and attenuation of the blood vessels were common, but bone spicule-like pigmentation was often mild or lacking. Most patients had nonrecordable electroretinogram responses and constriction of visual fields upon diagnosis. Bandah-Rozenfeld et al. (2010) suggested that modifier genes and/or environmental factors might play a role in this variable retinal phenotype.
MappingBy homozygosity mapping, Gu et al. (1999) found close linkage of the disorder in an Indian family to several markers on chromosome 2, with a maximum 2-point lod score of 3.07 at theta = 0.0 with D2S380. Linkage and haplotype analysis indicated that the locus, designated RP28, maps to 2p15-p11.
By homozygosity mapping in 20 families from Israel and the Palestinian territories segregating autosomal recessive RP, Bandah-Rozenfeld et al. (2010) found large homozygous regions on chromosome 2p; they identified 2 haplotypes that shared an approximately 4-Mb homozygous region overlapping the RP28 locus, an interval containing 22 annotated genes.
Molecular GeneticsUsing traces of DNA from 1 of the patients with retinitis pigmentosa (RP) mapping to 2p15-p11 studied by Gu et al. (1999), Langmann et al. (2010) analyzed the candidate gene FAM161A and identified a homozygous mutation (R229X; 613596.0001). The mutation was present in all 4 affected members of the family, whereas unaffected relatives were either heterozygous or carried wildtype alleles. Screening of FAM161A in 118 patients from Germany with recessive or sporadic forms of RP revealed the presence of another homozygous mutation (R437X; 613596.0002) in 3 patients; the mutation cosegregated with disease in the respective families and was not found in 400 ethnically matched control chromosomes.
In 20 families from Israel and the Palestinian territories segregating autosomal recessive RP mapping to chromosome 2p15, Bandah-Rozenfeld et al. (2010) analyzed 12 candidate genes and identified homozygosity or compound heterozygosity for 3 truncating mutations in the FAM161A gene (1355delCA, 613596.0003; R523X, 613596.0004; R596X, 613596.0005, respectively). The 1355delCA and R523X mutations were determined to be founder mutations in the Israeli Jewish population, and the 1355delCA had an estimated carrier frequency of 1:32 in individuals of North African Jewish ancestry.