Retinitis Pigmentosa Genetics

Oct 08, 2018

Retinitis pigmentosa is one of the commonest forms of inherited retina degenerative blindness worldwide. With the advent of molecular technologies it has become easier to identify the genetic defects associated with this condition.

Over a 100 genetic mutations have been found to affect the inheritance of this condition. Inheritance patterns are responsible for the different types of retinitis pigmentosa.

Inheritance patterns in retinitis pigmentosa

Inheritance may be:

Autosomal dominant
Autosomal recessive
X linked

Autosomal dominant has the maximum possibility of a parent-to-child transmission. Autosomal recessive classification is based on established inheritance between different family groups following principles of Mendelian genetics.

X linked inheritance is of further two types – Simplex and Multiplex. Simplex reflects isolated cases with one affected member. Multiplex is when at least two family members are affected.

Type 1 and Type 2 Retinitis pigmentosa

There are two types of retinitis pigmentosa depending on relative involvement of rods and cones photoreceptors. Patients with Type 1 RP display early and preferential loss of rod sensitivity and early signs such as diminished night vision. This condition also progresses lowly and leads to a region specific vision loss.

Patients with Type 2 RP have a progressive and combined loss of rod and cone sensitivity with onset in adulthood and later onset of diminished night vision.

Other organs

Retinitis pigmentosa may of two types - nonsyndromic, or "simple" when other organs are not affected or syndromic where other organs are involved (e.g. Usher syndrome). Nonsyndromic retinitis pigmentosa can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.

Digenic inheritance

There may be a rare digenic inheritance as well. Digenic inheritance is seen in persons with both a ROM1 mutation and an RDS gene mutation. Those with simplex cases result from autosomal dominant or X-linked mutation or autosomal recessive inheritance.

Table 1. Causes of Isolated Retinitis Pigmentosa by Mode of Inheritance

Mode of Inheritance	Proportion of All RP
Autosomal dominant RP (adRP)	15-25%
Autosomal recessive RP (arRP)	5-20%
X-linked RP (xlRP)	5-15%
Unknown: Simplex	40-50%
Digenic RP	Very rare

Genes and proteins in retinitis pigmentosa

Genes associated with retinitis pigmentosa code for proteins that are involved in the visual cycle where the photo reactive pigments are produced and recycled for effective vision. These genes also code for proteins that form photoreceptor structure and photoreceptor cell transcription factors.

Common mutations

Common mutations include those in the RHO gene. This gene codes for the rods and mutations may lead to autosomal dominant RP, autosomal dominant congenital stationary night blindness, or, rarely, autosomal recessive RP.

Similarly mutations of the RDS are also seen. This gene normally codes for peripherin and mutations lead to autosomal dominant RP, autosomal dominant macular degeneration, or digenic RP.

Some common genetic mutations and their associated retinitis pigmentosa types include:-

Autosomal Dominant retinitis pigmentosa - three gene mutations are responsible for autosomal dominant retinitis pigmentosa:-
- RHO 25 to 30%
- RP1 5 to 10%
- RDS 5 to 10%

There are more than 100 RHO mutations and P23H is commonly found in 10% of Americans with autosomal dominant retinitis pigmentosa. RDS mutations may lead to macular degeneration to complex maculopathies. Arg677stop and 2280del5 are the much studied RP1 mutations.

Autosomal Recessive retinitis pigmentosa – these are rarer genetic mutations. RPE65 (expressed in the RPE), and PDE6A and PDE6B cause 2-5% of cases and mutations in USH2A may account for up to 5% of autosomal recessive cases.
X-Linked retinitis pigmentosa – in this type common mutations are seen in RPGR (also called RP3) and RP2 genes. They account for 70-90% and 10-20%, respectively of all X linked cases.
Mitochondrial Genes Causing Nonsyndromic retinitis pigmentosa include mutations in the MT-TS2.
Digenic retinitis pigmentosa – this is caused by combined presence of a mutation in the RDS gene and a mutation in the ROM1 gene. The RDS mutation is commonly L185P.