Common genetic variation in KATNAL1 non-coding regions is involved in the susceptibility to severe phenotypes of male infertility.

BACKGROUND: Previous studies in animal models evidenced that genetic mutations of KATNAL1, resulting in dysfunction of its encoded protein, lead to male infertility through disruption of microtubule remodelling and premature germ cell exfoliation. Subsequent studies in humans also suggested a possible role of KATNAL1 single-nucleotide polymorphisms in the development of male infertility as a consequence of severe spermatogenic failure. OBJECTIVES: The main objective of the present study is to evaluate the effect of the common genetic variation of KATNAL1 in a large and phenotypically well-characterised cohort of infertile men because of severe spermatogenic failure. MATERIALS AND METHODS: A total of 715 infertile men because of severe spermatogenic failure, including 210 severe oligospermia and 505 non-obstructive azoospermia patients, as well as 1058 unaffected controls were genotyped for three KATNAL1 single-nucleotide polymorphism taggers (rs2077011, rs7338931 and rs2149971). Case-control association analyses by logistic regression assuming different models and in silico functional characterisation of risk variants were conducted. RESULTS: Genetic associations were observed between the three analysed taggers and different severe spermatogenic failure groups. However, in all cases, the haplotype model (rs2077011*C | rs7338931*T | rs2149971*A) better explained the observed associations than the three risk alleles independently. This haplotype was associated with non-obstructive azoospermia (adjusted p = 4.96E-02, odds ratio = 2.97), Sertoli-cell only syndrome (adjusted p = 2.83E-02, odds ratio = 5.16) and testicular sperm extraction unsuccessful outcomes (adjusted p = 8.99E-04, odds ratio = 6.13). The in silico analyses indicated that the effect on severe spermatogenic failure predisposition could be because of an alteration of the KATNAL1 splicing pattern. CONCLUSIONS: Specific allelic combinations of KATNAL1 genetic polymorphisms may confer a risk of developing severe male infertility phenotypes by favouring the overrepresentation of a short non-functional transcript isoform in the testis.

Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohort.

BACKGROUND: Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO, <5 million spermatozoa/mL semen) or non-obstructive azoospermia (NOA, complete lack of spermatozoa in the ejaculate without obstructive causes). OBJECTIVES: The main objective of the present study is to analyze in the Iberian population the effect of 6 single-nucleotide polymorphisms (SNPs) previously associated with NOA in Han Chinese through genome-wide association studies (GWAS) and to establish their possible functional relevance in the development of specific SpF patterns. MATERIALS AND METHODS: We genotyped 674 Iberian infertile men (including 480 NOA and 194 SO patients) and 1058 matched unaffected controls for the GWAS-associated variants PRMT6-rs12097821, PEX10-rs2477686, CDC42BPA-rs3000811, IL17A-rs13206743, ABLIM1-rs7099208, and SOX5-rs10842262. Their association with SpF, SO, NOA, and different NOA phenotypes was evaluated by logistic regression models, and their functional relevance was defined by comprehensive interrogation of public resources. RESULTS: ABLIM1-rs7099208 was associated with SpF under both additive (OR = 0.86, p = 0.036) and dominant models (OR = 0.78, p = 0.026). The CDC42BPA-rs3000811 minor allele frequency was significantly increased in the subgroup of NOA patients showing maturation arrest (MA) of germ cells compared to the remaining NOA cases under the recessive model (OR = 4.45, p = 0.044). The PEX10-rs2477686 SNP was associated with a negative testicular sperm extraction (TESE) outcome under the additive model (OR = 1.32, p = 0.034). The analysis of functional annotations suggested that these variants affect the testis-specific expression of nearby genes and that lincRNA may play a role in SpF. CONCLUSIONS: Our data support the association of three previously reported NOA risk variants in Asians (ABLIM1-rs7099208, CDC42BPA-rs3000811, and PEX10-rs2477686) with different manifestations of SpF in Iberians of European descent, likely by influencing gene expression and lincRNA deregulation.

Esophageal, pharyngeal and hemorrhagic complications occurring in anterior cervical surgery: Three illustrative cases.

BACKGROUND: The number of esophageal and pharyngeal perforations occurring in anterior cervical surgeries ranges from 0.25% to 1% and 0.2% to 1.2%, respectively. Symptoms usually appear postoperatively and are attributed to: Local infection, fistula, sepsis, or mediastinitis. Acute postoperative hematoma, although very rare (<1%), is the first complication to rule out due to its life-threatening complications (e.g. acute respiratory failure). CASE DESCRIPTION: Over a 36-year period, the author(s) described three severe esophageal/pharyngeal complications attributed to anterior cervical surgery. As these complications were appropriately recognized/treated, patients had favorable outcomes. CONCLUSIONS: Anterior cervical spine surgery is a safe approach and is associated with few major esophageal/pharyngeal complications, which most commonly include transient dysphagia and dysphonia. If symptoms persist, patients should be assessed for esophageal/pharyngeal defects utilizing appropriate imaging studies. Notably, even if the major complications listed above are adequately treated, optimal results are in no way guaranteed.

Dermoscopic features of melanocytic nevi in seven different anatomical locations in patients with atypical nevi syndrome.

BACKGROUND: Dermoscopic screening facilitates early detection of melanoma and is recommended in patients with multiple or atypical nevi. OBJECTIVES: To investigate whether dermoscopic features of acquired melanocytic nevi differ between six body sites (neck, axilla, pectoral area, shoulders, buttocks, legs) and the trunk. METHODS AND MATERIALS: One hundred six patients with atypical nevi syndrome from a Digital Dermoscopy Unit were evaluated for the presence of nevi in each of seven body sites, and nevi representative of each region were selected as the predominant nevi. Dermoscopic features of 684 melanocytic nevi located in seven different body sites were analyzed. RESULTS: Globular and globular-homogeneous pattern nevi showed a cephalad distribution. Nevi at the neck, axilla, shoulders, and pectoral area showed a higher proportion of globular and globular-homogeneous patterns than other locations (p < .001). Comma vessels were also more frequent on the neck, axillary area, and shoulders (p < .001). A reticular pattern was more frequent on caudal areas (legs, buttocks and lower back, and abdomen; p < .001). CONCLUSIONS: Dermoscopic differences were found in different body areas. This information should be considered in the evaluation of lesions in patients with atypical nevus syndrome.