Maternal Uniparental Disomy of Chromosome 1 with Reduction to Homozygosity of the LAMB3 Locus in a Patient with Herlitz Junctional Epidermolysis Bullosa

Abstract

Junctional epidermolysis bullosa (JEB) is an autosomal recessive disorder characterized by blister formation at the level of the lamina lucida within the cutaneous basement-membrane zone. Classic lethal JEB (Herlitz type [H-JEB]; OMIM 226700) is frequently associated with premature-termination-codon mutations in both alleles of one of the three genes (LAMA3, LAMC2, or LAMB3) encoding the subunit polypeptides (alpha3, beta3, and gamma2) of laminin 5. In this study, we describe a unique patient with H-JEB, who was homozygous for a nonsense mutation, Q243X, in the LAMB3 gene on chromosome 1 and who had normal karyotype 46,XY. The mother was found to be a carrier of the Q243X mutation, whereas the father had two normal LAMB3 alleles. Nonpaternity was excluded by use of 11 microsatellite markers from six different chromosomes. The use of 17 partly or fully informative microsatellite markers spanning the entire chromosome 1 revealed that the patient had both maternal uniparental meroisodisomy of a 35-cM region on 1q containing the maternal LAMB3 mutation and maternal uniparental heterodisomy of other regions of chromosome 1. Thus, the results suggested that reduction to homozygosity of the 1q region containing the maternal LAMB3 mutation caused the H-JEB phenotype. The patient was normally developed at term and did not show overt dysmorphisms or malformations. This is the first description of uniparental disomy of human chromosome 1.

A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

“…This is no surprise since most known cases have been uncovered on the basis of a reduction to homozygosity leading mainly to recessive traits (Table 3). From this clinically biased sample, it would appear that the chromosome1 Mendelian outlaws stem not only from the rescue of trisomies caused by maternal meiotic nondisjunction 31,40,42 but also from maternal nullisomies complemented by paternal monosomy duplications, 38,44 -47 a mechanism much rarer for chromosomes 18 and 21, as already discussed. Besides, a paternal meiotic involvement at the origin of these cases is also rather surprising, with 2n genotypes presumably arising from the correction of paternally induced trisomies 35,49 or from mitotic complementations of the monosomies resulting from a meiotic loss of the paternal member.…”

“…It is hard therefore to state the level of contribution of the various uniparental pairs to the overall occurrence of recessive disorders. As an indication, among some series of recessive conditions studied, such an aetiology was found in one of 61 cases of junctional epidermolysis bullosa of Herlitz, nearly 2%, 31 in one of 55 cases of cystic fibrosis, again 2% 55 and in two of 54 cases of cartilage -hair hypoplasia, about 4%. 33 …”

“…mutations of the LAMB3 locus on chromosome 1q32.2, encoding the subunit polypeptide gamma 2 of lamin 5, account for three of the 13 recorded instances of reduction to homozygosity of that member! 31,45,48 The relatively high incidence of cystic fibrosis, for which four of six UPDs seven are responsible 7,55 -57 may be biased as a result of the many segregation studies carried out for counselling in CF families, increasing the chances of detecting such events. All these disparate remarks point to the fact that the nondisjunctional meiotic mechanisms, central to the occurrence of the isodisomy process, vary strongly among the different chromosome members as shown for some on Table 4, inspired from Jacobs and Hassold.…”

Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1

“…Other UPD mechanisms, ie non-disjunction events during meiosis I or II in one parent, followed by gametic complementation, or trisomy rescue 14,15 will lead to heterodisomy. This is the third case of chromosome 1 maternal UPD, 16,17 whilst only one chromosome 1 paternal UPD has been reported so far. 18 Although this represent a small sample size, this difference might alternatively be related to the high frequency of chromosome 1 paternal nullisomy (0.25%) observed in the population.…”

“…This strengthens the observation made in two other settings which suggests that there are no imprinted gene(s) in maternally derived chromosome 1. 16,17 In the first reported case, absence of imprinting was observed in a 2-month-old infant 17 and in a young adult in the second Chromosome 1 isodisomy in CHS t case. 16 Pericentromeric heterodisomy with partial isodisomy characterised these two latter cases, whereas the paternal chromosome 1 UPD reported has pericentromeric isodisomy and distal heterodisomy.…”