Mus musculus Raw sequence reads
Missense mutations in SMCHD1, a chromatin regulator required for X-chromosome inactivation and autosomal gene silencing, cause congenital arhinia (absent nose), yet the developmental consequences of the disease-associated variants remain poorly defined. Here we use a mouse model to characterize the most common arhinia-associated mutation, p.Leu141Phe. Homozygous Smchd1L141F males were recovered at Mendelian ratios, exhibited normal growth, and displayed no detectable placental abnormalities. In contrast, homozygous Smchd1L141F females were markedly underrepresented in adulthood (~1%), indicating female-biased lethality. At embryonic day 16.5, female mutant homozygotes were present at expected frequencies but demonstrated intrauterine growth restriction with significantly reduced fetal crown rump length and placental weights. Histopathological assessment of the placenta showed thinning of the junctional zone, depletion of glycogen cell trophoblasts, and fewer secondary parietal trophoblast giant cells in mutant female placentas. In contrast, male placentas were unaffected. Immunohistochemistry confirmed normal SMCHD1 abundance and nuclear localization across genotypes. Bulk RNA-sequencing identified extensive transcriptional dysregulation in female mutant placentas (636 differentially expressed genes), including downregulation of prolactin/placental lactogen hormones (Prl7b1, Prl7c1, Prl4a1, Prl2b1) and lineage-specific transcription factors (Cdx2, Ets2, Ascl2). Male mutants exhibited relatively limited transcriptomic alterations. Thus, a SMCHD1 missense mutation caused sexually dimorphic placental dysfunction which lead to female-biased perinatal lethality. These findings implicate impaired endocrine function as a mechanism for female vulnerability. This knock-in model provides an in vivo platform for investigating human SMCHD1 variants in development and disease.