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The SRY gene (sex-determining region on the Y chromosome; MIM *480000) is responsible for initiating male gonadal development. However, only 15-20% of the cases of XY gonadal dysgenesis are due to mutations in its sequence. Recently, heterozygous mutations in the NR5A1 gene (nuclear receptor subfamily 5, group A, member 1; MIM +184757) have been described in association with ovarian failure and disorders of testis development with or without adrenal failure. Here we describe a case of XY complete gonadal dysgenesis due to a p.D293N homozygous mutation in the NR5A1 gene, with normal STY and no adrenal failure.
To date, 12 cases of heterozygous Ser72Leu mutations in the peripheral myelin protein 22 have been reported in patients suffering from severe demyelinating form of Charcot-Marie-Tooth disease (CMT1) and congenital hypomyelinating neuropathy (CHN) [MIM# 605253]. In the present study we report two cases of de novo S72L mu­tations in the PMP22 gene detected in patients of Polish origin suffering from CMT1 disease.
Mitochondrial homeostasis, resulting from fusion and fission processes together with mitophagy and mitogenesis, are widely studied nowadays. This is probably because we know more and more about the role of mitochondria in metabolic diseases (diabetes, hypertension), neurodegeneration (Parkinson’s Disease, Alzheimer’s Disease), but also in broad spectrum of inherited neurological syndromes (CharcotMarie-Tooth). In our studies we aimed to examine the expression pattern of particular mitochondrial proteins, mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), in mouse tissues. We aim to verify, whether potential differences in expression of those proteins can by implicated in pathomechanism of Charcot-Marie-Tooth type 2A neuromyopathy, related to mitofusion 2 gene mutations. Mitofusins are mitochondrial GTPases, implicated in fusion of outer mitochondrial membrane. In this process, mitofusins juxtapose two mitochondria by combining homo- and heterodimers at the surface of two outer mitochondrial membranes. Although there is 63% homology between mitofusins, it is proved, that they show some different functions. As Mfn1 KO present more severe aberrations in mitochondrial network formation than Mfn2 deficient cells, Mfn1 is considered to have stronger fusion activity. It is also suspected, that it is Mfn1 that links fusion of outer and inner mitochondrial membranes. Nevertheless, Mfn2, but not Mfn1, is present at endoplasmic reticulum (ER). Mfn2 tethers ER to mitochondria facilitating calcium flux and (indirectly) autophagy. Moreover, Mfn2 seems to have some regulatory effect on cell cycle, beyond its fusion activity and its lower expression seems to correlate with insulin resistance and hyper proliferation in hypertension. So, the question is, how much these two proteins can replace each other while playing so different roles? Moreover, it is suggested that CMT2A predominantly affects peripheral nerves because mutated, malfunctioned Mfn2 is insufficiently compensated by Mfn1 due to its low expression particularly in this type of tissue. To discuss this issue, we have investigated the expression of Mfn1 and Mfn2, as well as protein content, in tissues, performing Real Time PCR and Western Blot studies. Preliminary data from Western blot analysis displayed equally high relative level of both mitofusins in nervous system (dorsal root ganglia, cerebral cortex, cerebellum, spinal cord) in comparison to peripheral organs (muscle, heart, liver, kidney, skin). Moreover, Mfn1 expression seems significantly lower in dorsal root ganglia, which are well established model of peripheral nervous system. This phenomenon was not observed for other tissues, even from central nervous system. So it seems quite possible, that axonal damage of peripheral nerves in CMT2A, may be observed due to the poor compensation of dysfunctional Mfn2 by fully functional Mfn1, which is not expressed at sufficient level. The project was supported by NSC grant NN402474640
The methyl CpG binding protein 2 (MECP2), protein that binds to methylated DNA sequences and represses the expression of specific genes, is essential for normal function of mature nerve cells. The protein is encoded by MECP2 gene and its mutations are responsible for approximately 90% of all Rett syndrome (RTT) cases. RTT is a neurodevelopmental disorder that affects mainly girls. Its characteristic features include arrested psychomotor development (6–18 months), congenital impairment, loss of speech, characteristic stereotypical movements, regression of gained skills and other neuropsychiatric abnormalities. Nineteen patients with primary clinical diagnosis of RTT were referred for molecular examination. The analysis of MECP2 gene included direct sequencing of exons 2–4 and deletion/ duplication analysis using MLPA method. In nine patients we have found seven known point mutations, including three nonsense substitutions in four individuals (p.R168X, p.R255X, and p.R270X in 2 cases) and three missense changes leading to amino acids substitutions in the methyl-binding domain (p.R133C, p.K135E, p.T158M) or in the transcriptional repression domain (p.R306C in 2 cases). In three other patients, a partial deletion of MECP2 was found, including a deletion of exons 3 and 4 (encompassing 2 to 67 kb) and two different deletions of exon 4, encompassing 44 bp and 1 to 7.3 kb, respectively. Together, we were able to confirm the clinical diagnosis of Rett syndrome in 12 cases. The significant presence of large deletions encompassing entire exons suggests that the MLPA analysis should be performed as an important part of the molecular diagnosis in Rett syndrome.
Among 57 mutations in the peripheral myelin protein 22 gene (PMP22) identified so far in patients affected by Charcot-Marie-Tooth disease (CMT), only 8 have been shown to segregate with a mixed phenotype of CMT and hearing impairment. In this study, we report a new Ser112Arg mutation in the PMP22 gene, identified in a patient with early-onset CMT and slowly progressive hearing impairment beginning in the second decade of life. We suggest that the Ser112Arg mutation in the PMP22 gene might have a causative role in the early-onset CMT with hearing impairment. Thus, our study extends the spectrum of CMT phenotypes putatively associated with PMP22 gene mutations.
Diagnosis of Parkinson’s disease (PD) is often problematic because clinically it can be difficult to distinguish idiopathic PD from the other extrapyramidal disorders. It is known, that PD is caused either by environmental and genetic factors . Genetic mutations are the cause of familial form of PD and include genes PARK1-PARK18. The etiology of sporadic PD (SPD) is still not clear, but it is currently assumed that genetic susceptibilities, may be involved. It is suggested, that in pathogenesis of the SPD beside SNCA and PARK2 genes, may be involved also SPR (sepiapterin reductase gene) [PARK3] and HTRA2 (HTRA serine peptidase 2 gene)[PARK13] genes. The HTRA2 gene, also known as Omi, was found to be associated with PD in German population. However, some studies have indicated that some variants of HTRA2 may not be related to PD. SPR gene, which is located in the PARK3 linkage region is inconsistently associated with a risk of PD but significance of mutations in this gene as well as HTRA2 in PD is still not clear. The aim of the study was the analysis of the frequency of T637A/G SPR as well G421T, G1195A and C1210T mutations in HTRA2 gene in Polish patients with PD and in control group. Peripheral blood was collected from 89 patients with PD clinical diagnosis (42F and 47M, the avr. age 62 ± 10.15 years), and from 113 healthy donors (79F and 7M, the avr. age 55.5 ± 9.54 years). Genomic DNA was isolated using standard protocols. Genotyping was performed by PCR/RFLP using specific primers and restriction enzymes (SsiI, MboII, MvaI, MspI) and sequencing. The SPR gene analysis detected T637A mutation in 3 (3%) PD patients compared to 2 (2%) persons in the control group. Moreover, mutations G421T and G1195A of HTRA2 gene have been identified in 3 (3%) [G421T – 1%, G1195A – 2%] patients with PD and none of controls. Analysis of C1210T HTRA2 mutation detected no mutated variant both in PD patients group and in control group. It was also observed that the stage of the disease was 1–2 in Hoehn and Yahr scale and response to L-dopa was good in patients with T637A SPR and G421T, G1195A HTRA2 mutations. It was also observed some tendency for depression manifestation in PD patients with T637A SPR mutation. It can be concluded, that mutations of SPR and HTRA2 genes probably may be one of the risk factor for manifestation of PD. Thus, the results of this study suggest that analysis of T637A SPR and G421T, G1195A HTRA2 genes mutations may be an additional diagnostic and prognostic factor in PD patients in the future.
Nijmegen breakage syndrome (NBS), a rare autosomal recessive chromosomal instability disorder, is caused by mutations in the NBN gene. Most patients known so far are of Slavic origin and carry the major founder mutation c.657-661del5. Due to an unexpectedly high incidence of NBS patients (homozygous for the c.657-661 del5 mutation) in a Northeast Bavarian region in Southeast Germany, we estimated the prevalence of this mutation in this area and compared itto another German region. We found a high carrier frequency of 1/176 for the c.657-661 del5 mutation among newborns in Northeast Bavaria, while the frequency of the mutation in Berlin was 1/990. We further studied families from a Slavic population isolate, the Sorbs, in the Lusatian region in Northeast Saxony, and revealed a prevalence of thee.657-661 del5 mutation of 1/34. Whereas the Slavic origin of the Sorbs has been known, we attribute the surprisingly high frequencies of c.657-661 del5 mutation in Bavaria (similar to frequencies of this mutation in various Eastern European countries) to a high percentage of people of Slavic origin in Northeast Bavaria.
The mechanical properties of the red cell are accounted for by its membrane and its membrane skeleton, the latter being a protein network that laminates the inner surface of the lipid bilayer. Hereditary spherocytosis (HS) is the most common of congenital hemolytic anemias. The spherocytes have a reduced lifespan due to their spheroidal shape that alters their resistance and elastic deformability. It is now established that the responsible alterations affect most often the ANK1 gene that encodes erythroid ankyrin. A noticeable HS subset is associated with a reduction of the anion exchanger 1 (AE1, or band 3), due to mutation in the corresponding gene, the EPB3 gene. Much more rarely, HS goes along with a sharp reduction, if not the absence, of protein 4.2. This stigmata results either from mutations in the DNA sequences that encode the binding site of the AE1 cytoplasmic domain for protein 4.2, or from mutations of protein 4.2 gene itself, the ELP42 gene. Mutations responsible for HS lie rarely or exceptionally in the spectrin β- or the α-genes (SPTB and SPTA1 genes, respectively). Elucidation of new HS mutations is presently at its height. It casts light on the function of specific domains within the various proteins involved, and on the integration of protein structure and function at the cellular scale.
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