{"title":"A recessive deleterious missense variant in PEX7 causes a lethal form of chondrodysplasia in Bazadaise cattle","authors":"Cécile Grohs, Stéphanie Minéry, Sébastien Fritz, Mekki Boussaha, Aurélien Capitan","doi":"10.1111/age.70035","DOIUrl":null,"url":null,"abstract":"<p>The term ‘bulldog calves’ colloquially refers to a heterogeneous group of skeletal malformations, typically characterized by severe craniofacial deformities reminiscent of the brachycephalic appearance of Bulldog dogs. These conditions include type II achondrogenesis, spondyloepimetaphyseal dysplasia, and rhizomelic chondrodysplasia punctata (RCDP) caused by mutations of <i>COL2A1</i>, <i>ACAN</i>, and <i>GNPAT</i>, respectively (Boulling et al., <span>2025</span>; Bourneuf et al., <span>2017</span>; Cavanagh et al., <span>2007</span>; Daetwyler et al., <span>2014</span>).</p><p>Since 2020, four ‘bulldog calves’ (two males, two females) have been reported to the French National Observatory for Bovine Abnormalities by the breeding society of the local Bazadaise breed. All were stillborn and exhibited disproportionate dwarfism, characterized by craniofacial dysmorphism, shortened limbs with hypermobile joints, and low birth weight despite a normal gestation length (~20–25 kg vs. 40 kg; Figure 1a,b). Ear biopsies were obtained from three cases, but no specimens were available for comprehensive pathological examination due to rapid carcass disposal.</p><p>Pedigree analysis using the PEDIG software package (Boichard, <span>2002</span>) identified a single common ancestor four to seven generations back across all lineages, supporting a recessive mode of inheritance (Figure 1c).</p><p>Homozygosity mapping using the Illumina EuroGMD SNP array (Boichard et al., <span>2018</span>) and established methods (Boulling et al., <span>2025</span>; Mesbah-Uddin et al., <span>2019</span>) revealed a significant peak on chromosome 9, defined by a 74-marker haplotype homozygous in all cases and none of 223 controls (Bonferroni-adjusted <i>p</i> < 0.01; Figure 1d).</p><p>The whole genome of an affected calf was sequenced as described by Boulling et al. (<span>2025</span>). After excluding variants present in a control panel of 1869 cattle from over 70 non-Bazadaise breeds (dataset described in Besnard et al., <span>2024</span>), 16 candidate variants remained within the associated interval (NC_037336.1:73 454 255–79 825 274 bp; ARS-UCD1.2 genome assembly; Table S1). Among them, only the NC_037336.1:g.74831677G>T substitution in the gene encoding peroxisomal biogenesis factor 7 (PEX7), leading to a p.Asp205Tyr amino acid change, was predicted to be deleterious (SIFT score = 0.01). Interestingly, mutations in <i>PEX7</i> and four other genes involved in peroxisomal protein import or ether phospholipid synthesis (<i>PEX5</i>, <i>AGPS</i>, <i>FAR1</i>, and <i>GNPAT</i>) have been implicated in human RCDP (de Vet et al., <span>1998</span>; Devi et al., <span>2021</span>; Dodt et al., <span>1995</span>; Motley et al., <span>1997</span>; Ofman et al., <span>1998</span>; Purdue et al., <span>1997</span>).</p><p>Furthermore, as outlined in the introduction, our team identified a recessive <i>GNPAT</i> variant as the cause of the RCDP subtype of bulldog calves in Aubrac cattle (Boulling et al., <span>2025</span>; https://omia.org/OMIA002958/9913/), and retrospective comparison of images revealed striking phenotypic similarities between the Aubrac and Bazadaise cases.</p><p>Upon verification, the two additional affected calves were confirmed to be homozygous for the NC_037336.1:g.74831677T allele using a custom probe incorporated into the EuroGMD array. Analysis of 236 213 animals from 19 breeds revealed that this variant allele was exclusively detected in Bazadaise cattle with an estimated frequency of 3.9% (see Table S2 for details and probe design information).</p><p>Finally, targeted genotyping of Bazadaise artificial insemination bulls revealed that Bull G was the primary source of the defect. According to pedigree records of 14 222 calves born between 2020 and 2024, Bull G is the second most influential sire in the breed, contributing an estimated 6.9% to its genetic makeup.</p><p>In conclusion, we report a recessive deleterious missense variant in <i>PEX7</i> associated with a lethal form of chondrodysplasia in Bazadaise cattle, which could be classified as RCDP (See https://omia.org/OMIA002973/9913/).</p><p><b>Cécile Grohs:</b> Investigation; visualization; writing – review and editing. <b>Stéphanie Minéry:</b> Formal analysis. <b>Sébastien Fritz:</b> Formal analysis; resources. <b>Mekki Boussaha:</b> Formal analysis. <b>Aurélien Capitan:</b> Conceptualization; formal analysis; investigation; data curation; visualization; supervision; funding acquisition; writing – original draft.</p><p>This work was supported by the Effitness project funded by APIS-GENE.</p><p>The authors declare no conflicts of interest.</p>","PeriodicalId":7905,"journal":{"name":"Animal genetics","volume":"56 4","pages":""},"PeriodicalIF":2.1000,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/age.70035","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Animal genetics","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/age.70035","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"AGRICULTURE, DAIRY & ANIMAL SCIENCE","Score":null,"Total":0}
引用次数: 0
Abstract
The term ‘bulldog calves’ colloquially refers to a heterogeneous group of skeletal malformations, typically characterized by severe craniofacial deformities reminiscent of the brachycephalic appearance of Bulldog dogs. These conditions include type II achondrogenesis, spondyloepimetaphyseal dysplasia, and rhizomelic chondrodysplasia punctata (RCDP) caused by mutations of COL2A1, ACAN, and GNPAT, respectively (Boulling et al., 2025; Bourneuf et al., 2017; Cavanagh et al., 2007; Daetwyler et al., 2014).
Since 2020, four ‘bulldog calves’ (two males, two females) have been reported to the French National Observatory for Bovine Abnormalities by the breeding society of the local Bazadaise breed. All were stillborn and exhibited disproportionate dwarfism, characterized by craniofacial dysmorphism, shortened limbs with hypermobile joints, and low birth weight despite a normal gestation length (~20–25 kg vs. 40 kg; Figure 1a,b). Ear biopsies were obtained from three cases, but no specimens were available for comprehensive pathological examination due to rapid carcass disposal.
Pedigree analysis using the PEDIG software package (Boichard, 2002) identified a single common ancestor four to seven generations back across all lineages, supporting a recessive mode of inheritance (Figure 1c).
Homozygosity mapping using the Illumina EuroGMD SNP array (Boichard et al., 2018) and established methods (Boulling et al., 2025; Mesbah-Uddin et al., 2019) revealed a significant peak on chromosome 9, defined by a 74-marker haplotype homozygous in all cases and none of 223 controls (Bonferroni-adjusted p < 0.01; Figure 1d).
The whole genome of an affected calf was sequenced as described by Boulling et al. (2025). After excluding variants present in a control panel of 1869 cattle from over 70 non-Bazadaise breeds (dataset described in Besnard et al., 2024), 16 candidate variants remained within the associated interval (NC_037336.1:73 454 255–79 825 274 bp; ARS-UCD1.2 genome assembly; Table S1). Among them, only the NC_037336.1:g.74831677G>T substitution in the gene encoding peroxisomal biogenesis factor 7 (PEX7), leading to a p.Asp205Tyr amino acid change, was predicted to be deleterious (SIFT score = 0.01). Interestingly, mutations in PEX7 and four other genes involved in peroxisomal protein import or ether phospholipid synthesis (PEX5, AGPS, FAR1, and GNPAT) have been implicated in human RCDP (de Vet et al., 1998; Devi et al., 2021; Dodt et al., 1995; Motley et al., 1997; Ofman et al., 1998; Purdue et al., 1997).
Furthermore, as outlined in the introduction, our team identified a recessive GNPAT variant as the cause of the RCDP subtype of bulldog calves in Aubrac cattle (Boulling et al., 2025; https://omia.org/OMIA002958/9913/), and retrospective comparison of images revealed striking phenotypic similarities between the Aubrac and Bazadaise cases.
Upon verification, the two additional affected calves were confirmed to be homozygous for the NC_037336.1:g.74831677T allele using a custom probe incorporated into the EuroGMD array. Analysis of 236 213 animals from 19 breeds revealed that this variant allele was exclusively detected in Bazadaise cattle with an estimated frequency of 3.9% (see Table S2 for details and probe design information).
Finally, targeted genotyping of Bazadaise artificial insemination bulls revealed that Bull G was the primary source of the defect. According to pedigree records of 14 222 calves born between 2020 and 2024, Bull G is the second most influential sire in the breed, contributing an estimated 6.9% to its genetic makeup.
In conclusion, we report a recessive deleterious missense variant in PEX7 associated with a lethal form of chondrodysplasia in Bazadaise cattle, which could be classified as RCDP (See https://omia.org/OMIA002973/9913/).
术语“牛头犬犊牛”通俗地指的是一组不同种类的骨骼畸形,典型特征是严重的颅面畸形,让人想起牛头犬的短头畸形外观。这些疾病包括由COL2A1、ACAN和GNPAT突变分别引起的II型软骨发育不全、脊椎骺端发育不良和点状根状软骨发育不良(RCDP) (Boulling et al., 2025;Bourneuf et al., 2017;Cavanagh et al., 2007;Daetwyler et al., 2014)。自2020年以来,当地Bazadaise品种育种协会向法国国家牛畸形观测站报告了四只“牛头犬幼崽”(两只雄性,两只雌性)。所有胎儿均为死产,并表现出不成比例的侏儒症,其特征是颅面畸形,四肢缩短,关节活动过度,尽管妊娠期正常,但出生体重低(~ 20-25 kg vs. 40 kg;图1 a, b)。对3例病例进行了耳部活检,但由于尸体处理迅速,没有标本进行全面的病理检查。使用PEDIG软件包(Boichard, 2002)进行系谱分析,在所有谱系中发现了一个四到七代的共同祖先,支持隐性遗传模式(图1c)。使用Illumina EuroGMD SNP阵列(Boichard et al., 2018)和既定方法(Boulling et al., 2025;Mesbah-Uddin等人,2019)在9号染色体上发现了一个显著的峰值,所有病例中都有74个标记单倍型纯合,223个对照中没有(bonferroni调整p <; 0.01;图1 d)。按照Boulling等人(2025)的描述,对一头受影响小牛的全基因组进行了测序。在排除了来自70多个非bazadaise品种的1869头牛的控制面板中存在的变异后(数据集描述于Besnard等人,2024年),16个候选变异仍在相关区间内(nc_0373361:73 454 255-79 825 274 bp;ARS-UCD1.2基因组组装;表S1)。其中,只有编码过氧化物酶体生物发生因子7 (peroxisomal biogenesis factor 7, PEX7)的基因NC_037336.1:g.74831677G>;T的替换导致p.Asp205Tyr氨基酸的改变,被预测为有害的(SIFT评分= 0.01)。有趣的是,PEX7和其他四个参与过氧化物酶体蛋白输入或醚磷脂合成的基因(PEX5、AGPS、FAR1和GNPAT)的突变与人类RCDP有关(de Vet et al., 1998;Devi等人,2021;Dodt et al., 1995;Motley et al., 1997;Ofman et al., 1998;Purdue et al., 1997)。此外,正如引言中概述的那样,我们的团队发现了一种隐性GNPAT变异是奥布拉克牛牛头犬犊牛RCDP亚型的原因(Boulling等人,2025;https://omia.org/OMIA002958/9913/),并对图像进行回顾性比较,发现Aubrac和Bazadaise病例在表型上有惊人的相似性。经验证,另外两只受影响的小牛被证实为NC_037336.1:g的纯合子。74831677T等位基因使用定制探针并入EuroGMD阵列。对来自19个品种的236 213头牛的分析显示,该变异等位基因仅在巴扎达兹牛中检测到,估计频率为3.9%(详细信息和探针设计信息见表S2)。最后,对巴扎达兹人工授精公牛进行基因分型分析,结果表明G牛是该缺陷的主要来源。根据2020年至2024年间出生的14222头小牛的血统记录,公牛G是该品种中第二大最有影响力的父系,对其基因构成的贡献约为6.9%。总之,我们报告了一种与巴扎达斯牛软骨发育不良致死形式相关的PEX7隐性有害错意义变异,可归类为RCDP(见https://omia.org/OMIA002973/9913/).C caccile Grohs:调查;可视化;写作——审阅和编辑。正式分析。s bastien Fritz:形式分析;资源。Mekki Boussaha:形式分析。aur lien Capitan:概念化;正式的分析;调查;数据管理;可视化;监督;资金收购;写作-原稿。本工作由api - gene资助的Effitness项目支持。作者声明无利益冲突。
期刊介绍:
Animal Genetics reports frontline research on immunogenetics, molecular genetics and functional genomics of economically important and domesticated animals. Publications include the study of variability at gene and protein levels, mapping of genes, traits and QTLs, associations between genes and traits, genetic diversity, and characterization of gene or protein expression and control related to phenotypic or genetic variation.
The journal publishes full-length articles, short communications and brief notes, as well as commissioned and submitted mini-reviews on issues of interest to Animal Genetics readers.