Brachydactylia with symphalangism,probably autosomal recessive

Summary Association, in one patient, of the following malformations: brachydactylia of all segments but terminal phalanges; proximal symphalangism of many fingers and toes; abnormalities of carpal and tarsal bones; partial duplication of both big toes; mild hypertelorism. Genetic transmission seems to be recessive autosomal.     

Multilocus autosomal sex determination

The two basic one locus sex determination models, diploid individual sex determination and parental sex determination, are generalized to the multilocus framework. As in the single locus case, it is established that there are two classes of polymorphic equilibria, equilibria with even sex ratio and equilibria with equal allele frequencies in the two sexes. The condition for external stability of this second class equilibria to invasion by a new mutant allele is that a new appropriately averaged sex ratio near the equilibrium be moved closer to the even sex ratio. However, stable polymorphisms with noneven sex ratio are not those that have a sex ratio as close as possible to 1/2, in contrast to the single locus case.Research supported in part by NIH grants GM 28016 and GM 10452 and a grant from the U.S.-Israel Binational Science Foundation     

Admixture estimates for Caracas, Venezuela, based on autosomal, Y-chromosome, and mtDNA markers

The present Venezuelan population is the product of admixture of Amerindians, Europeans, and Africans, a process that was not homogeneous throughout the country. Blood groups, short tandem repeats (STRs), mtDNA, and Y-chromosome markers have been used successfully in admixture studies, but few such studies have been conducted in Venezuela. In this study we aim to estimate the admixture components of samples from two different socioeconomic levels from Caracas, Venezuela's capital city, compare their differences, and infer sexual asymmetry in the European Amerindian union patterns. Gene frequencies for blood groups ABO and Rh (CDE) and for the STRs VWA, F13A01, and FES/FPS and mtDNA and Y-chromosome haplogroups were studied in a sample of 60 individuals living in Caracas, taken from a private clinic (high socioeconomic level), and 50 individuals, also living in Caracas, drawn from a public maternity clinic (low socioeconomic level). The admixture analysis for the five autosomal markers gives a high European component (0.78) and an almost negligible African sub-Saharan component (0.06) for the high socioeconomic level, whereas for the low socioeconomic level the sub-Saharan, European, and Amerindian components were 0.21, 0.42, and 0.36, respectively. Estimates of admixture based on mtDNA and Y-chromosome markers reveal that the Amerindian contribution to these Caracas samples is almost entirely through females, because the Y-chromosome Amerindian and African sub-Saharan chromosomes found in this study were scarce. Our study reveals that the identification of the grandparents' geographic origin is an important methodological aspect to take into account in genetic studies related to the reconstruction of historical events.     

Aspermia,associated with a presumably balanced X/autosomal translocation

Summary A new case of X/autosome translocation in a male patient is described. Azoospermia and Klinefelter like stigmata can be explained as a consequence of the balanced translocation, or by disturbed X-chromosomal inactivation during spermiogenesis.

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Zusammenfassung Es wird über einen neuen Fall einer X/Autosom-Translokation beim Mann berichtet. Azoospermie und Klinefelter-ähnliche Stigmata können unmittelbar auf die balancierte Translokation zurückgeführt werden oder Folge einer durch die Translokation gestörten X-chromosomalen Inaktivierung während der Spermiogenese sein.

     

Mouse autosomal trisomy: two's company, three's a crowd.

Autosomal trisomy causes a large proportion of all human pregnancy loss and so is a significant source of lethality in the human population. The autosomal trisomy syndromes each have a different phenotype and are probably caused by the effects of specific genes that are present in three copies, rather than the normal two. Identifying these genes will require the application of classical genetic and new genome-manipulation approaches. Recent advances in chromosome engineering are now allowing us to create precisely defined autosomal trisomies in the mouse, and so provide new routes to identifying the critical, dosage-sensitive genes that are responsible for these highly deleterious, yet very common, syndromes.     

Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.     

Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum.

To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations.     

Molecular mechanisms of autosomal recessive hypercholesterolemia

PURPOSE OF REVIEW: Autosomal recessive hypercholesterolemia (ARH) is a rare Mendelian dyslipidemia characterized by markedly elevated plasma LDL levels, xanthomatosis, and premature coronary artery disease. LDL receptor function is normal, or only moderately impaired in fibroblasts from ARH patients, but their cultured lymphocytes show increased cell-surface LDL binding, and impaired LDL degradation, consistent with a defect in LDL receptor internalization. Recently, the disorder was shown to be caused by mutations in a phosphotyrosine binding domain protein, ARH, which is required for internalization of low density lipoproteins in the liver. This review summarizes the findings of new investigations into the pathophysiology and molecular genetics of ARH. RECENT FINDINGS: All mutations that have been characterized to date preclude the synthesis of a full-length protein. GST-pulldown experiments indicate that the phosphotyrosine binding domain of ARH interacts with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR, and that conserved motifs in the C-terminal portion of the protein bind to clathrin and to the beta2-adaptin subunit of AP-2. SUMMARY: The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.     

Mutations for the autosomal recessive and autosomal dominant forms of polycystic kidney disease are not allelic

Summary The autosomal dominant form of polycystic kidney disease (ADPKD) has been linked to the -globin gene locus on 16p. Linkage studies between the autosomal recessive type (ARPKD) and the 3 HVR of the -globin gene cluster showed that the ARPKD and ADPKD are not allelic.     

Genetics of autosomal recessive intellectual disability

In the last few years, next-generation sequencing has led to enormous progress in deciphering monogenic forms of intellectual disability. Autosomal dominant intellectual disability (ADID) and X chromosomal intellectual disability (XLID) have been the focus of research. Apart from metabolic disorders, autosomal recessive intellectual disability (ARID) is still behind, probably because it is more heterogeneous and less prevalent in industrial populations. The prevalence of ARID in a cohort of affected children of an outbred population is estimated to be about 10%, with an upward tendency in still unclarified cases. The risk for ARID in children of first cousins or closer is a magnitude higher than for children of unrelated parents. Taken together, it seems that children of related parents are at a 2 to 3 times higher risk for ID. There are no prevalent ARID genes, pathways, or protein complexes and the functions of the affected proteins are very diverse and limited not only to neurological aspects. Thus, in a regular case, there is no reasoning for picking a few genes for a first diagnostic step, and a genetic diagnosis of ID in general, and ARID specifically, is better made using large panels or exome sequencing. In addition, in the last few months, evidence has been growing that many ARID genes are pleiotropic and that the resulting phenotypes may have a broad spectrum. For an exhaustive deciphering of the genetics of ARID, we suggest research at the level of single genes rather than large meta-analyses.     

Balanced autosomal translocations and ovarian dysgenesis

We report two unrelated women with gonadal dysgenesis, and a (6;15)(p21.3;q15) and a (8;9)(p11.2;q12) balanced translocation, respectively. The patients were of normal stature and showed no phenotypic abnormality or malformation other than ovarian failure. We are not aware of other reports of balanced autosomal translocations associated with gonadal dysgenesis in women. The occurrence of chromosome anomaly and sterility in the two females may be coincidental. However, studies on mouse gametic progression indicate that balanced autosomal translocations can cause oocyte degeneration and reduction of reproductive lifespan. On the basis of these observations, we cannot exclude that the ovarian failure in our patients is the result of oocyte degeneration because of as yet unidentified consequences of the balanced translocations.