Rivolta Carlo, Berson Eliot L, Dryja Thaddeus P
Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114, USA.
Arch Ophthalmol. 2002 Nov;120(11):1566-71. doi: 10.1001/archopht.120.11.1566.
To evaluate a form of nonmendelian inheritance in a patient with retinitis pigmentosa (RP).
Direct DNA sequencing of the USH2A coding region and microsatellite analysis of polymorphic markers from chromosome 1 and other chromosomes.
A patient with RP without hearing loss caused by the homozygous mutation Cys759Phe in the USH2A gene on chromosome 1q was found to be the daughter of a noncarrier mother and a father who was heterozygous for this change. Further evaluation with microsatellite markers revealed that the patient had inherited 2 copies of chromosome 1 from her father and none from her mother. The paternally derived chromosome 1's were heteroallelic from the centromere of chromosome 1 to the proximal short and long arms. The distal regions of the short and long arms of chromosome 1 were homoallelic, including the region of 1q with the mutant USH2A allele. This genetic pattern is compatible with a phenomenon of uniparental primary heterodisomy with regions of homozygosity arising through a nondisjunction event during paternal meiosis I and subsequent trisomy rescue or gamete complementation. A paternal second cousin of the patient also had RP and also had an identical heterozygous mutation in the USH2A gene in the same codon. However, the analysis of an isocoding polymorphism 20 base pairs away and closely linked microsatellite markers in the patient and family members indicated that the 2 mutant alleles are unlikely to be identical by descent and that the 2 relatives fortuitously had RP and a mutation in the same codon of the USH2A gene.
This family illustrates that recessive RP without hearing loss can rarely be inherited from only 1 unaffected carrier parent in a nonmendelian manner.
The genetic counseling of families with recessively inherited eye diseases must take into consideration the possibility that an unaffected heterozygous carrier can have an affected offspring homozygous for the same mutation, even if the carrier's spouse has wild-type alleles at the disease locus.
评估一名视网膜色素变性（RP）患者的一种非孟德尔遗传形式。
对USH2A编码区进行直接DNA测序，并对1号染色体和其他染色体上的多态性标记进行微卫星分析。
发现一名1q染色体上USH2A基因纯合突变Cys759Phe导致的无听力损失的RP患者，其母亲为非携带者，父亲为该突变的杂合子。用微卫星标记进一步评估发现，该患者从父亲那里继承了2条1号染色体，而未从母亲那里继承。来自父亲的1号染色体从1号染色体着丝粒到近端短臂和长臂是杂合等位基因。1号染色体短臂和长臂的远端区域是纯合等位基因，包括携带突变USH2A等位基因的1q区域。这种遗传模式与单亲原发性异源二体现象相符，即通过父本减数分裂I期间的不分离事件以及随后的三体挽救或配子互补产生纯合区域。该患者的一位父系二表亲也患有RP，并且在同一密码子的USH2A基因中也有相同的杂合突变。然而，对患者及其家庭成员中距离该密码子20个碱基对的等编码多态性和紧密连锁的微卫星标记进行分析表明，这两个突变等位基因不太可能是同源的，这两名亲属是偶然患有RP且在USH2A基因的同一密码子发生了突变。
这个家系表明，无听力损失的隐性RP很少能以非孟德尔方式仅从一名未受影响的携带者亲本遗传而来。
对于隐性遗传性眼病家族的遗传咨询必须考虑到这样一种可能性，即未受影响的杂合携带者可能会有一个因相同突变而纯合的患病后代，即使携带者的配偶在疾病位点具有野生型等位基因。
