Incontinentia pigmenti (IP) and r(X). Tentative mapping of the IP locus to the X juxtacentromeric region

A 45,X/46,X,r(X) mosaicism was observed in an incontinentia pigmenti (Bloch-Sulzberger form) female patient, with mental retardation, short stature, and minor dysmorphisms. This observation is compatible with the regional assignment of the incontinentia pigmenti locus to the juxta-centromeric region of the X, the r(X) being of very small size.     

Incontinentia pigmenti (type 1) and X;5 translocation.

The authors present a 5-year-old girl with total absence of speech, dysmorphic features, pigmented lesions on the legs, an abnormal EEG and otherwise normal intelligence representing a mild form of type 1 Incontinentia pigmenti associated with an (X;5) (p11.2;q35.2) apparently balanced translocation prenatally diagnosed. The seven previous translocation type 1 IP patients are reviewed and all have the same Xp11 breakpoint. Somatic cell hybrids have been made to further study this breakpoint and further define the putative type 1 IP gene.     

Two cases of X/autosome translocation in females with incontinentia pigmenti

Summary We report two unrelated girls who present some clinical features of severe incontinentia pigmenti (IP), with characteristic skin pigmentation. Both have balanced de novo X/autosome translocations involving band Xp11. The coincidence of the probable de novo expression of an X-linked disorder in these two girls with translocations involving similar breakpoints on the X chromosome suggests that this band may be the site of the IP gene locus.     

Molecular cloning of Xp11 breakpoints in two unrelated mentally retarded females with X;autosome translocations

Mental retardation is a very common and extremely heterogeneous disorder that affects about 3% of the human population. Its molecular basis is largely unknown, but many loci have been mapped to the X chromosome. We report on two mentally retarded females with X;autosome translocations and breakpoints in Xp11, viz., t(X;17)(p11;p13) and t(X;20)(p11;q13). (Fiber-) FISH analysis assigned the breakpoints to different subbands, Xp11.4 and Xp11.23, separated by approximately 8 Mb. High-resolution mapping of the X- chromosome breakpoints using Southern blot hybridization resulted in the isolation of breakpoint-spanning genomic subclones of 3 kb and 0. 5 kb. The Xp11.4 breakpoint is contained within a single copy sequence, whereas the Xp11.23 breakpoint sequence resembles an L1 repetitive element. Several expressed sequences map close to the breakpoints, but none was found to be inactivated. Therefore, mechanisms other than disruption of X-chromosome genes likely cause the phenotypes.     

Mosaicism 45,X/46,X, t dic(Xp:Xp) in a girl with short stature

An eight-year-old girl with marked short stature and no apparent stigmata of Turner syndrome was investigated. Clinical features include bilateral epicanthic folds, frontal bossing, prominent ears and normal intelligence. Ultrasound scanning revealed an apparently normal vagina, streak ovaries and no uterus. Bone age was normal. Karyotype analysis of peripheral blood lymphocytes showed mos 45,X/46,X tdic(Xp:Xp) in the ratio 66:34, respectively. In addition, three cells with different abnormal X chromosomes were present which possibly originated from a 46,XX clone. Replication of the duplicated X chromosome was consistently late and symmetrical. Buccal smear confirmation of the karyotype showed Barr body negative in 90% and large or bipartite in 10% of the cells. Karyotypes of the parents were normal. The clinical manifestations in cases of Xp deletion due to terminal rearrangement associated with or without a 45,X cell line are discussed.     

Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to a distal subregion of band Xp11.21 by PCR analysis of somatic cell hybrids containing X; autosome translocations.

The erythroid-specific (ALAS2) and housekeeping (ALAS1) genes encoding delta-aminolevulinate synthase have recently been mapped to chromosomes Xp21.1----q21 and 3p21, respectively. The erythroid-specific gene is a candidate for mutations resulting in X-linked sideroblastic anemia. Analysis of DNA from hybrid clones containing translocations in the region Xp11.21----Xq21.3 permitted the finer localization of the ALAS2 gene with respect to other loci and breakpoints within this region. These studies localized the ALAS2 gene to the distal subregion of Xp11.21 in Interval 5 indicating the following gene order: Xpter-OATL2-[L62-3A, Xp11.21; A62-1A-4b, Xp11.21]-(ALAS2, DXS323)-[B13-3, Xp11.21; C9-5, Xp11.21]-(DXS14, DXS429)-DXS422-(DXZ1, Xcen). Thus, the reported linkage of acquired sideroblastic anemia and sideroblastic anemia with ataxia to Xq13 presumably results from genes other than ALAS2.     

Dermatoglyphic peculiarities in patients with hypomelanosis of Ito (Incontinentia pigmenti achromians). A new case

We have analyzed the dermatoglyphic aspects of a patient affected by hypomelanosis of Ito (Incontinentia pigmenti achromians — HI) and of his healthy mother, and have compared our findings with those of the only three other cases in whom such studies had been done. It appeared that hypomelanosis of Ito shows anomalous dermatoglyphic peculiarities: a larger number of ulnar loops and the frequent absence of patterns in thenar, II and III interdigital areas. However, the absence of some interdigital triradii, particularly of d triradius, seems to be the most distinctive character. Since the timing of embryonal life during which d triradius should be formed is between 16 and 17 weeks, it seems highly probable that some developmental abnormality might occur at this point in HI. Moreover, the present analysis allows to support some hypotheses already proposed in the literature, concerning the modalities of determination of the absence of d triradius. The observed concomitance with some dermatoglyphic findings, such as the absence of other palmar triradii and the absence of interdigital patterns, led us to suggest that such characteristics could be connected each other, having perhaps a common genetical basis or undergoing the same microenvironmental effects.     

Analysis of spreading of inactivation in eight X autosome translocations utilizing the high resolution RBG technique

Summary Eight X autosome translocations were studied with replication banding to localize spreading of late replication into the autosomal segments. Partial spreading into the autosomal segment was seen in four translocations and no spreading of late replication was seen in four translocations. In those translocations with partial spreading of late replication into the autosomal segment, late replication did not always spread continuously from the X chromosome breakpoint throughout the autosome. Instead, it appeared to skip some bands and affect others. The data on the pattern of replication, taken to indicate also a spread of inactivation into these autosomal segments, correlated well with the clinical data in most cases and suggest that spreading of late replication is often incomplete and may be discontinuous.     

Hypomagensemia with secondary hypocalcemia in a female with balanced X;9 translocation: mapping of the Xp22 chromosome breakpoint

Magnesium-dependent hypocalcaemia (HSH), a rare inherited disease, is caused by selective disorders of magnesium absorption. Both X-linked and autosomal recessive modes of inheritance have been reported for HSH; this suggests a genetically heterogeneous condition. A balanced de novo t(X;9)(p22;q12) translocation has been reported in a female manifesting hypomagnesemia with secondary hypocalcemia. In a lymphoblastoid cell line, derived from this patient, the normal X chromosome is preferentially inactivated, suggesting that the patient's phenotype is caused by disruption of an HSH gene in Xp22. In an attempt to define more precisely the position of the X breakpoint, we have constructed a hybrid cell line retaining the der(X)(Xqter-Xp22.2::9q12-9qter) in the absence of the der(9) and the normal X chromosome. Southern blot analysis of this hybrid and in situ hybridization on metaphase chromosomes have localized the breakpoint between DXS16 and the cluster (DXS207, DXS43), in Xp22.2. Thus, if a gene involved in HSH resides at or near the translocation breakpoint, our findings should greatly facilitate its isolation.     

Strategy for constructing somatic hybrids isolating the two derivative chromosomes in X;autosome translocations. Application to a female patient t(X;5) with Hunter syndrome

X; autosomal translocations are excellent tools for genetic analysis because of the easy selection of clones isolating the derivative bearing the HPRT gene in somatic cell hybrids. We have developed a strategy to select clones isolating the other derivative avoiding fastidious and time consuming technics, mainly based on immunofluorescent screening using MIC 2 and MIC 5 antigenic markers and we have succeeded in isolating in a rodent context the two X;5 translocated derivative chromosomes of a female patient with Hunter syndrome. The location of MIC 5 gene was specified between the IDS and G6PD DXS369 (RN1), DXS296 (VK21c), and DXS304 (U62), DXS52 and F8c (F814) are proximal and distal from the breakpoint disrupting the IDS gene respectively.     

Duchenne muscular dystrophy (DMD) in a female with an X/autosomal translocation: Further evidence that the DMD locus is at Xp21

An isolated case of Duchenne muscular dystrophy in a female who has a de novo t(X;5)(p21;q35) translocation is described. The similarities between this patient and four previously reported females with Duchenne muscular dystrophy are discussed. It is concluded that the locus for Duchenne muscular dystrophy is at Xp21 and, furthermore, that this site may be particularly susceptible both to chromosome breakage and exchange and to gene mutation.     

Translocation (X;9)(p11;q34) in a girl with incontinentia pigmenti (IP): implications for the regional assignment of the IP locus to Xp11?

A t(X;9)(p11;q34) is reported in a girl with incontinentia pigmenti (IP). The X breakpoint is at p11.21. Although no similar case has been reported, this breakpoint may be significant insofar IP is considered an X-linked dominant mutation and could be of help in a specific X DNA probes study.     

Y;autosome translocations and mosaicism in the aetiology of 45,X maleness: assignment of fertility factor to distal Yq11

Summary Three 45,X males have been studied with Y-DNA probes by Southern blotting and in situ hybridization. Southern blotting studies with a panel of mapped Y-DNA probes showed that in all three individuals contiguous portions of the Y chromosome including all of the short arm, the centromere, and part of the euchromatic portion of the long arm were present. The breakpoint was different in each case. The individual with the largest portion (intervals 1–6) is a fertile male belonging to a family in which the translocation is inherited in four generations. The second adult patient, who has intervals 1–5, is an azoospermic, sterile male. These phenotypic findings suggest the existence of a gene involved in spermatogenesis in interval 6 in distal Yq11. The third case, a boy with penoscrotal hypospadias, has intervals 1–4B. In situ hybridization with the pseudoautosomal probe pDP230 and the Y chromosome specific probe pDP105 showed that Y-derived DNA was translocated onto the short arm of a chromosome 15, 14, and 14, respectively. One of the patients was a mosaic for the 14p+ translocation chromosome. Our data and those reported by others suggest the following conclusions based on molecular studies in eight 45,X males: The predominant aetiological factor is Y;autosome translocation observed in seven of the eight cases. As the remaining case was a low-grade mosaic involving a normal Y chromosome, the maleness in all cases was due to the effect of the testis determing factor, TDF. There is preferential involvement of the short arm of an acrocentric chromosome (five out of seven translocations) but other autosomal regions can also be involved. The reason why one of the derivative translocation chromosomes becomes lost may be that it has no centromere.     

A case of (X;15) translocation diagnosed as a paracentric inversion of Xp: diagnostic revision with FISH.

In 1990 we reported the case of a 17 years old girl with growth retardation, overweight and primary amenorrhea, presenting a de novo chromosomal rearrangement cytogenetically characterized as a paracentric inversion of the short arm of X chromosome. The FISH analyses that were recently performed, revealed that in fact our patient presented a case of unbalanced translocation, 46,X, t(X;15)(p11.2; q15).     

Localization of DNA sequences to a region within Xp11.21 between incontinentia pigmenti (IP1) X-chromosomal translocation breakpoints.

Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by developmental anomalies of the tissues and organs derived from embryonic ectoderm and neuroectoderm. An IP locus, designated IP1, probably resides in Xp11.21, since five unrelated patients with nonfamilial IP have been identified who possess constitutional de novo reciprocal X;autosome translocations involving Xp11.21. We have used a series of somatic cell hybrids containing the rearranged chromosomes derived from three of the five IP1 patients, along with other hybrid cell lines, to map probes in the vicinity of the IP1 locus. Five anonymous DNA loci--DXS422, DXS14, DXS343, DXS429, and DXS370--have been mapped to a region within Xp11.21, between two IP1 X-chromosomal translocation breakpoints; the IP1 t(X;17) breakpoint is proximal (centromeric) to this region, and the IP1 t(X;13) and t(X;9) X-chromosomal breakpoints lie distal to it. While no IP1 translocation breakpoint has yet been identified by pulsed-field gel electrophoretic (PFGE) analysis, an overlap between three probes--p58-1, 7PSH3.5, and cpX210--has been detected, placing these probes within 125 kb. Four probes--p58-1, 7PSH3.5, cpX210, and 30CE2.8--have been helpful in constructing a 1,250-kb PFGE map of the region between the breakpoints; these results suggest that the IP1 X-chromosomal translocation breakpoints are separated by at least this distance. The combined somatic cell hybrid and PFGE analyses we report here favor the probe order DXS323-(IP1 t(X;13), IP1, t(X;9]-(DXS422, DXS14, DXS343, DXS429, DXS370)-(IP1 t(X;17), DXZ1). These sequences provide a starting point for identifying overlapping genomic sequences that span the IP1 translocation breakpoints; the availability of IP1 translocation breakpoints should now assist the cloning of this locus.     

Three Finnish incontinentia pigmenti (IP) families with recombinations with the IP loci at Xq28 and Xp11

The locus (IP2) for the hereditary form of incontinentia pigmenti (IP) has been mapped to Xq28 by linkage analysis. We studied three IP families with polymorphic markers in the Xq28 region. In two families we observed recombination between the marker loci and IP. In the third family no crossing overs were seen and linkage to the Xq28 region could not be excluded. The other IP locus (IP1) has been mapped to Xp 11.21, because of sporadic cases of IP with X-chromosomal alterations involving Xp11.21. To check whether this locus is linked to IP in these families, we used polymorphic markers in the Xp11 region. In all three families recombinations were observed, thus excluding linkage to this locus in these IP families.     

Nullisomy for the distal portion of Xp in a male child with a X/Y translocation

Summary An unbalanced X/Y translocation was found in a male child with malformed external genitalia and in his mother, who are respectively nullisomic and monosomic for the distal portion of Xp and have the translocated distal segment of Yq in excess. The loss of the distal portion of Xp is supposed to be the cause of the phenotypic abnormalities present in these subjects. The phenotype of our subjects is compared with those of the other cases of X/Y translocation described in the literature.