👤 Knut Brockmann

Microtubule-actin cross-linking factor 1 (MACF1) is a large protein of the spectraplakin family, which is essential for brain development. MACF1 interacts with microtubules through the growth arrest-specific 2 (Gas2)-related (GAR) domain. Heterozygous MACF1 missense variants affecting the zinc-binding residues in this domain result in a distinctive cortical and brain stem malformation. Evidence for other MACF1-associated disorders is still limited. Here, we present a cohort of 45 individuals with heterozygous or bi-allelic MACF1 variants to explore the phenotypic spectrum and assess possible pathogenic relevance. We observe that de novo heterozygous missense variants in the EF-hand domains also result in distinctive brain malformation and provide experimental evidence that variants in the EF-hand/GAR module increase microtubule binding, suggestive of a toxic gain of function. Notably, no phenotype-genotype correlation was possible for the remaining heterozygous variants in other domains. A clinical review of eight families with bi-allelic variants reveals a possible complex neurodevelopmental syndrome of the central and peripheral nervous systems. In these individuals, bi-allelic variants mostly affect the Plakin domain. Furthermore, RNA sequencing and chromatin immunoprecipitation (ChIP) analyses of human fetal brain tissue reveal five MACF1 isoforms with region-specific expression, differing in their exon 1 transcription start sites but splicing to a common exon 2. This differential expression explains the frontal-predominant lissencephaly in an individual with a homozygous stop-gain in exon 1 (MACF1-204: c.70C>T [p.Arg24∗]), as this isoform is preferentially expressed in the frontal cortex. We conclude that MACF1-related disorders are strictly linked to domain function and the level of transcript expression, explaining the observed wide clinical heterogeneity. Show less

The German Black Pied cattle (DSN) is an endangered dual-purpose breed valued for its genetic diversity and high milk fat and protein content. However, due to competition with higher-yielding dairy breeds, the DSN population has declined, leading to its designation as an endangered breed. While previous research has focused on the milk production traits of DSN, this study aims to address meat traits to further understand the genetic determination of the dual-purpose characteristics of the breed. We conducted genome-wide association studies on 669 DSN bulls to identify genetic loci associated with birth weight, BW, and BW gain at different growth stages. Using imputed whole-genome sequencing data, we identified 14 quantitative trait loci across ten chromosomes. Significant associations were found for birth weight on chromosomes 5 and 18, for body weight at 3 weeks (BW Show less

The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and the metabolic syndrome. This study aimed to identify genetic variants associated with liver weight, liver triglycerides, and body weight using the obese BFMI sub-line BFMI861-S1. BFMI861-S1 mice are insulin resistant and store ectopic fat in the liver. In generation 10, 58 males and 65 females of the advanced intercross line (AIL) BFMI861-S1xB6N were phenotyped under a standard diet over 20 weeks. QTL analysis was performed after genotyping with the MiniMUGA Genotyping Array. Whole-genome sequencing and gene expression data of the parental lines was used for the prioritization of positional candidate genes. Three QTLs associated with liver weight, body weight, and subcutaneous adipose tissue (scAT) weight were identified. A highly significant QTL on chromosome (Chr) 1 (157-168 Mb) showed an association with liver weight. A QTL for body weight at 20 weeks was found on Chr 3 (34.1-40 Mb) overlapping with a QTL for scAT weight. In a multiple QTL mapping approach, an additional QTL affecting body weight at 16 weeks was identified on Chr 6 (9.5-26.1 Mb). Considering sequence variants and expression differences, Sec16b and Astn1 were prioritized as top positional candidate genes for the liver weight QTL on Chr 1; Met and Ica1 for the body weight QTL on Chr 6. Interestingly, all top candidate genes have previously been linked with metabolic traits. This study shows once more the power of an advanced intercross line for fine mapping. QTL mapping combined with a detailed prioritization approach allowed us to identify additional and plausible candidate genes linked to metabolic traits in the BFMI861-S1xB6N AIL. By reidentifying known candidate genes in a different crossing population the causal link with specific traits is underlined and additional evidence is given for further investigations. Show less