Premature Ovarian Failure 2b

A number sign (#) is used with this entry because of evidence that premature ovarian failure-2B (POF2B) is caused by mutation in the POF1B gene (300603). One such family has been reported.

For a phenotypic description and a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).

Clinical Features

Lacombe et al. (2006) described a Lebanese family in which 5 sisters varying in age from 29 to 41 years had POF presenting with primary amenorrhea. In at least 2 of the sisters, osteoporosis and 'dental problems' were documented. The proband continued to increase in height until she began sex hormone treatment, and was 181 cm tall at age 31.

Mapping

Using whole genome single-nucleotide polymorphism (SNP) typing and homozygosity by descent mapping, Lacombe et al. (2006) established linkage of POF in 5 Lebanese sisters to Xq21.1-q21.3.3, within the POF2 region (see 300511).

Molecular Genetics

In 5 affected members of a Lebanese family with POF, Lacombe et al. (2006) identified a point mutation in the candidate gene POF1B (R329Q; 300603.0001) and demonstrated that this mutation disrupts the normal binding of POF1B to nonmuscle actin filaments. Affected family members were homozygous for the mutation, whereas unaffected family members were heterozygous. In a control group of 92 women of the same ethnicity as the familial cases, Lacombe et al. (2006) found 4 heterozygotes for the R329Q variant. The authors stated that the high frequency of this genotype in Lebanon increases the likelihood of the presence of R329Q in the homozygous state.

Population Genetics

Lacombe et al. (2006) estimated the allele frequency of the R329Q variant of POF1B in Lebanon to be 2.2%, giving a predicted rate of homozygosity in that population of 0.048%.