A five-generation family with sacral agenesis and spina bifida: possible similarities with the mouse T-locus.

In man, a malformation that recalls some of the defects associated with T/t mutants in the mouse is sacral agenesis. We report on a family with a high incidence of sacral malformation, ranging from a complete absence of the sacrum (SA), with or without spina bifida aperta, to a spina bifida occulta (SBO) that could only be detected by x-ray. The condition appeared in a man with four children who were all affect, and thereafter, to varying degrees, in 17 of his 28 descendants. Segregation analysis has been performed in this family, using the Elston and Stewart transmission probability model [1971]. The two traits (SA and SBO) were first studied separated and then together. A fully penetrant major dominant gene is show to cause SA. When the phenotypes SA and SBO are considered together, Mendelian transmission is rejected. This could be explained genetically by two alternative hypotheses: genetic heterogeneity or a dominant major gene transmitted in excess by heterozygotes (tau Aa A = 0.896), suggesting a segregation distortion property of an allele at a T-like locus.

[Genetic study of GM2 gangliosidosis (Tay-Sachs and Sandhoff) by the study of the hexosaminidases of the Sandhoff-rodents hybrids (mouse and hamster)]. / Contribution à l'étude génétique des gangliosidoses GM2 (Tay-Sachs et Sandhoff) par l'étude des hexosaminidases des hybrides Sandhoff-rongeurs (souris et hamster)

The electrophoretic pattern of human fibroblast extracts displays three bands (cathode to anode) of hexosaminidase: Hex B, Hex A, Hex C in normal strains, only one B band in Tay-Sachs strains, and only one C band in Sandhoff strains. The author's observations on rodent-Sandhoff cellular hybrids agree with the hypothesis made by others: Hex B = (beta beta)n; Hex A = (alpha beta)n; and Hex B = (alpha alpha) n. The mutation occurred in the alpha chain in Tay-Sachs disease and in the beta chain in Sandhoff disease. When mannose phosphate isomerase (MPI) is present, and therefore Hex C because of the well known MPI - Hex C synteny, a new hexosaminidase band called "Hex A fast" is seen in Sandhoff-hamster hybrids, while a "Hex A like" band is seen in Sandhoff-mouse hybrids. Both bands are absent from parental cells. It is suggested that "Hex A fast" and "Hex A like" are human-rodent hybrid hexosaminidases: "Hex A fast" = (alpha beta')n; "Hex A like" = (alpha beta's)n with the assumption that hamster HB' = (beta' beta')n and mouse Hex B'S = (beta's beta's)n. The specific anti Hex A = anti (alpha beta); the non-specific anti Hex A = anti Hex B = anti (beta); the anti (alpha) would be absent or weak. This explains the reactivity of the anti-Hex A against Hex A and Hex B, but not against Hex C.

[Genetic control of hexosaminidases]. / Le controle genetique des hexosaminidases.

The authors present the results they obtained which interspecific cell hybrids. The hexosaminidases A, B and C, seem to be under the control of the two genes alpha and beta, B and CS constituing homopolymers (beta beta)n and (alpha alpha)n, A being a heteropolymer (alpha beta)n. The isozyme CF, particularly abundant in fetal tissues and found also in Tay-Sachs by some authors is, in all probability, under independent genetic control.

[Permissivity of mouse-man hybrid cell clones to three enteroviruses: poliovirus II, coxsackie B3 and echovirus 11. Role of human chromosome F. 19 (author's transl)]. / Permissivité de clones cellulaires hybrides homme-souris à trois entérovirus : poliovirus II, coxsackie B3 et echovirus 11. Rôle de chromosome humain F 19

The permissivity of human cells to enteroviruses is linked to the presence of specific cell receptors. Owing to the chance elimination of human chromosomes, the man-mouse hybrid cells may be permissive or not depending on the genome responsible for synthesis of the receptors, and whether it has been conserved or not. By comparison of the cytopathogenic effects and virus production after inoculation of the viruses Polio II, Echo 11 and Coxsachie B3 to various hybrid strains, we observed an identity of the spectrum of permissivity to these three viruses. The enzyme study revealed a very high correlation between this permissivity and expression by the clones of the human glucose phosphate isomerase enzyme, of which the structural gene was localised on chromosome F 19. These results suggest the presence on this chromosome of a gene or syntenic genes, governing the synthesis of specific cell receptors to the viruses studied.

[Localization of enolases 1 and 2 on chromosomes 1 and 12 respectively by the analysis of human-mouse hybrids]. / Localisation des énolases 1 et 2 respectivement sur les chromosomes 1 et 12 par l'analyse des hybrides homme-souris.

The study of enolase in man-mouse somatic hybrids confirms synteny between ENO1 and the markers on human chromosome 1 (AK2, PGM1, Pep-C) and synteny between ENO2 and the markers on human chromosome 12 (LDHB, Pep-B). The study also shows that the different enolase bands observed in mouse cell strains (Cl1D, R4, A9, 3T3), in hamster cell strains (CH, V79/4, A3), and in 3 of the different bands observed in human fibroblasts have a dimeric structure. The formation of these enolase bands depends on genes at two different loci alpha and beta. The hamster cell line CH (HGPRT) showed a rare enolase phenotype with a two-banded pattern in the intermediate region, a triple-banded pattern in the slow region, and one single isozyme in the fast region. This hamster strain is heterozygous for the first locus and homozygous for the second one. The relationship between these different enolase bands is as follow: in the slow "a" zone, alpha1alpha1,alpha1 alpha2,alpha2alpha2; in the intermediate "i" zone, alpha1beta1, alpha2beta1; and, in the fast "b" zone, beta1beta1. It appears that the frequency of heterozygotes for the alpha or beta loci in man is very low. Of 32 unrelated fibroblast strains investigated, none was found to be heterozygous for the alpha or beta locus.

Isolation of 37 single-copy DNA probes from human chromosome 6 and physical mapping of 11 probes by in situ hybridization.

Fifty-five single-copy DNA probes were isolated from the library LL06NS01, which was constructed from a complete HindIII digest of a flow-sorted human chromosome 6. Because chromosomes from a human x Chinese hamster somatic cell hybrid were used as the starting material for the flow-sorting, the library could be expected to contain some contaminating Chinese hamster DNA as well as DNA from human chromosomes other than 6. Thirty-seven of the 55 probes, however, were shown to map to human chromosome 6 by Southern blot hybridization with DNA from a panel of somatic cell hybrids. Eleven of the probes were mapped further by in situ hybridization. Four probes were localized to the short arm of chromosome 6, six to the long arm, and one to the centromeric region.

The human placental protein 14 (PP14) gene is localized on chromosome 9q34.

PP14 protein (placental protein 14) is abundantly secreted by the human endometrium under the influence of progesterone. Human PP14 is homologous to beta-lactoglobulin, the main component of equine, bovine, and ovine milk whey. A genomic PP14 probe (PP14G1) was used for the chromosome assignment of the PP14 gene. Somatic hybrid cells enabled PP14G1 to be assigned to chromosome 9. In situ hybridization further refined this assignment to 9q34. The localization of the PP14 gene in the region of the ABO locus is consistent with the linkage described in bovines between beta-lactoglobulin and the J blood group (homologous to the human ABO group).

Assignment of NADH-cytochrome b5 reductase (DIA1 locus) to human chromosome 22.

NADH-cytochrome b5 reductase (DIA1, EC. 1.6.2.2) from human fibroblasts and from Chinese hamster cells, both identified by immunologic studies, were clearly distinguished after polyacrylamide gel isoelectro-focusing followed by staining for NADH diaphorase activity. In thirteen independent man-hamster hybrids, the human enzyme DIA1 presented a positive correlation with the human chromosome G22. Eight hybrids were DIA1(+) G22(+) and five hybrids were DIA1(-) G22(-). These data agree with the recent assignment of DIA1 to chromosome G22 by Fisher et al. (1977a). We assume that this newly assigned locus codes for both soluble and microsomal forms of NADH-cytochrome b5 reductase.

[Assignment of the creatine kinase BB gene to chromosome 14 by man-rodent cell hybridization (author's transl)]. / Localisation du gène de la créatine kinase, BB sur le chromosome 14 par l'analyse des hybrides homme-rongeur.

The value of man-rodent hybrids for detecting creatine kinase BB (CKBB) was greatly increased by the use of an agar technique, in extended incubation (20 hours) with a concentrated solution of creatine as substrate (8 mg/ml instead of 1 mg/ml as usual). The selection of a man-rodent hybrid without discordant between chr. 14 and nucleoside phosphorylase (NP) (a marker of this chromosome) contributed efficiently to the detection of the positive correlation between CKBB and chr. 14/NP. Among 22 independent hybrids, the following were observed : 8 NP + CKBB+, 3 NP + CKBB(+), 11 NP-CKBB- and 6 chr. 14 + CKBB+, 2 chr. 14 + CKBB(+), 11 chr. 14 CKBB-, 2 chr. 14/CKBB+ and 1 chr. 14/CKBB(+). The presence of the chromosome was noted + or - according to its presence in more or less than 30% of the cells. These results show that the gene for CKBB is located on chr. 14 and that the presence of this single chr. 14 is sufficient for the expression of human CKBB in man-rodent hybrids. Discordant results reported by others (Povey et al., 1979) may be due to the weakness of the human CKBB detection in man-rodent hybrids or to the bad conservation of this enzyme.

Investigations on the chromosomal localizations of the human and chimpanzee interferon genes: possible role of chromosomes 9 and 13.

Analysis of a great number of independent hamster-human and mouse-chimpanzee somatic cell hybrid clones confirms the role of chromosome 9 as carrying one or more primate beta interferon genes. The presence of chromosome 13 in producing hybrids and its absence in all non producing clones must be kept in mind for future studies. The strong negative regulation of interferon production in the parental hamster cells also affects the human gene product. The UV irradiation target for these regulatory genes is significantly greater than the structural genes responsible for interferon production.

Confirmation of the assignment of the gene for arylsulfatase A to chromosome 22 using somatic cell hybrids.

Human/hamster hybrid cell cultures were examined for the presence of ARSA and other marker enzymes. Many of these hybrids were also analyzed for human chromosomes. Our results confirm the assignment of ARSA to chromosome 22.

[Gene localization in the chimpanzee (Pan troglodytes). Comparison with the factor mapping of man (Homo sapiens)]. / Localisations géniques chez le chimpanzé (Pan troglodytes) Comparaison avec la carte factorielle de l'homme (Homo sapiens)

Ten independant cellular hybrids were obtained from Chimpanzee (Pan troglodytes) fibroblasts and the murine cell line C11D. The comparison of electrophoretic and cytogenetic studies showed that 9 markers with known localizations in Man could also be localized on the homologous chromosomes of the Chimpanzee: pyrophosphate hydratase (PPH), phosphoglucomutase-1 (PGM1), and peptidase-C (Pep-C) on the No. 1; malate dehydrogenase MDH(NAD) on the No. 2; lactico dehydrogenase-A (LDH-A) on the No. 11; lactico dehydrogenase-B (LDH-B) on the No. 12; thymidine kinase (TK) on the No. 17; superoxide dismutase-1 (SOD-1) on the No. 21; glucose-6-phosphate dehydrogenase (G6PD) on the X. The localization of mannose phosphate isomerase (MPI) on the No. 7 could be excluded. One discrepancy between Chimpanzee and Man was noted: the localization of superoxide dismutase-2 (SOD-2) on the 6 is excluded.

Chromosomal localization of human genes governing the interferon-induced antiviral state.

Interferon sensitivity of different normal and aneusomic human cells and of different mouse-human hybrids cells has been compared. G21 trisomic cells are more sensitive than diploid cells; whereas, on the contrary, triploid cells are normal in their human interferon sensitivity. Among other aneusomic cell lines tested, E16 trisomic cells are significantly less sensitive. These data are in favor of the hypotheses that the G21 chromosome carries genetic information for structural proteins involved in the receptor system for interferon, that there is a regulatory mechanism governing the antiviral state, and that the E16 chromosome is a possible candidate for carrying information for such a depressive regulatory mechanism. None of the chromosome abnormalities studies are involved with interferon synthesis.

[Confirmation of the localization on human chromosome F19 of a structural gene of poliovirus receptors]. / Confirmation de la localisation sur le chromosome humain F 19 d'un gène de structure des récepteurs de poliovirus

The study of permissivity for poliovirus and the study of enzymatic markers in man-mouse somatic cell hybrids presents a very positive correlation between the presence of the poliovirus receptor and the presence of a well known enzyme marker, the phosphoglucoseisomerase (GPI), localized on the human chromosome F 19.

A study of hexosaminadases in interspecific hybrids and in GM2 gangliosidosis with a discussion on their genetic control.

1. Hexosaminidases were studied by electrophoresis with different human fibroblast extracts. We found in the same conditions of detection and culture three bands from the cathode to the anode, namely Hex B, Hex A, Hex C for the normal fibroblast, Hex B for the two different Tay-Sachs and Hex C for the two unrelated Sandhoff patients. 2. The analysis of man-rodent hybrids (hamster and mouse with normal and Sandhoff human fibroblasts) indicates a probable synteny between MPI, Hex C, "Hex A fast", and "Hex A-like". "Hex A fast" is probably a man-hamster hybrid enzyme, "Hex A-like" a man-mouse enzyme. Our data agree with the model of Ropers and Schwantes (Hex C = (alphaalpha)n; Hex A = (alphabeta)n; Hex B = (betabeta)n). Probably Hex A-fast = (alphabeta')n with hamster Hex B' = (beta'beta')n; and Hex A-like = (alphabeta1)n with mouse Hex B1 = (beta1beta1)n; and probably n = 2 according to the tetrameric structure model of Tallman et al. (1974). 3. As an explanation of the results given by Poenaru et al. (anti Hex A reacts with Hex A and Hex B but not with Hex C) we propose the existence of a compound antigen (alphabeta) for Hex A. Anti Hex A specific = anti (alphabeta); anti Hex A non-specific = anti Hex B = anti B, anti alpha being absent or negligible. 4. In our opinion, the Tay-Sachs mutation opposes the alphaB association while the alphaalpha association is possible at a low rate or unstable; it is thus possible to observe Hex C in certain conditions, e.g. in foetal brain. 5. We present a discussion about the genetic control of hexosaminidases, GM2 gangliosidosis, and the possible localization of the different mutations in the variants.

[Localization of a structural locus of erythrocyte inorganic pyrophosphatase on chromosome 10 in man by the method of human-hamster cellular hybridization]. / Localisation d'un locus de structure de la pyrophosphatase inorganique "érythrocytaire" sur le chromosome 10 chez l'homme par la méthode d'hybridation cellulaire homme-hamster

The study of man-hamster hybrids puts forward a correlation between the activity of the erythrocyte inorganic pyrophosphatase and the presence of the human chromosome C 10, and on the other hand, a very positive correlation between the activity of this enzyme with the soluble glutamate-oxaloacetate transaminase (GOTS), already localized on the same chromosome.

Chromosome no. 1 of man and chimpanzee: identity of gene mapping for three loci: PPH, PGM1, and Pep-C.

Cytogenetic and biochemical analysis of 10 independant Chimpanzee-Mouse cell hybrids and of 18 subclones of one of these showed that PPH, PGM1 and Pep-C are localized on the Chimpanzee chromosome homologous to the human chromosome No. 1.

[Assignment of the genes of beta-glucuronidase, enolase-2 and phosphoglycerate kinase to chromosomes 7, 12 and X in the Chimpanzee]. / Localisation des gènes de la beta-glucuronidase, de l'énolase-2 et de la phosphoglycérate kinase sur les chromosomes 7, 12 et X du chimpanzé.

By cellular hybridization with C11D cells, the following gene assignments to specific chromosomes were demonstrated for the chimpanzee: beta-glucuronidase on chromosome 7, enolase-2 on chromosome 12, and the phosphoglycerate kinase on the X.

Assignment of the human coproporphyrinogen oxidase to chromosome 9.

By using somatic cell hybrids between human fibroblasts and hamster or mouse cells, we have assigned the gene for human coproporphyrinogen oxidase to chromosome 9.