Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5

doi:10.1007/s11684-023-1006-x

2024, Vol. 18

Issue (1) : 81-97 https://doi.org/10.1007/s11684-023-1006-x

Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5

Liwei Sun^1,^2,³, Xueting Yang¹, Amjad Khan^1,^4,^5,⁶(

), Xue Yu^1,⁷, Han Zhang^1,⁸, Shirui Han¹, Xiaerbati Habulieti¹, Yang Sun¹, Rongrong Wang¹(

), Xue Zhang¹

¹. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
². Chongqing Key Laboratory of Human Embryo Engineering, Center for Reproductive Medicine, National Key Clinical Speciality Construction Project (Obstetrics and Gynecology), Chongqing Health Center for Women and Children, Chongqing 400013, China
³. Chongqing Clinical Research Center for Reproductive Medicine, Women and Children’s Hospital of Chongqing Medical University, Chongqing 400013, China
⁴. Faculty of Biological Sciences, Department of Zoology, University of Lakki Marwat, Khyber Pakhtunkhwa 28420, Pakistan
⁵. Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72076, Germany
⁶. Alexander von Humboldt fellowship Foundation, Berlin 10117, Germany
⁷. Department of Pediatrics, the First Affiliated Hospital of Guangxi Medical University, Nanning 530000, China
⁸. Department of Laboratory Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China

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Abstract

Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine. Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation. Here, a Pakistani family with parental consanguinity was presented, characterized with severe intellectual disability (ID), spastic paraplegia, and deafness. Homozygosity mapping, integrated single nucleotide polymorphism (SNP) array, whole-exome sequencing, and whole-genome sequencing were performed, and homozygous variants in TMEM141 (c.270G>A, p.Trp90*), DDHD2 (c.411+767_c.1249-327del), and LHFPL5 (c.250delC, p.Leu84*) were identified. A Tmem141^{p.Trp90*/p.Trp90*} mouse model was generated. Behavioral studies showed impairments in learning ability and motor coordination. Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells. Transmission electron microscopy showed abnormal mitochondrial morphology. Furthermore, studies on a human in vitro neuronal model (SH-SY5Y cells) with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function, possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model. Conclusively, panoramic variation analysis revealed that multilocus genomic variations of TMEM141, DDHD2, and LHFPL5 together caused variable phenotypes in patient. Notably, the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.

Keywords neurodevelopmental disorder autosomal recessive intellectual disability consanguinity spastic paraplegia hearing loss TMEM141

Corresponding Author(s): Amjad Khan,Rongrong Wang

About author:

Li Liu and Yanqing Liu contributed equally to this work.

Just Accepted Date: 06 September 2023 Online First Date: 17 October 2023 Issue Date: 22 April 2024

Cite this article:

Liwei Sun,Xueting Yang,Amjad Khan, et al. Panoramic variation analysis of a family with neurodevelopmental disorders caused by biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5[J]. Front. Med., 2024, 18(1): 81-97.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1006-x
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I1/81

Fig.1 Electrophysiological test and Golgi staining of hippocampal neurons and cerebellar Purkinje cells. (A) a. Position of stimulation and recording pipettes in hippocampal slices. b. fEPSPs recorded for each condition before (baseline) and 60 min after the application of theta-burst stimulation (TBS) in the hippocampal sections of the WT and Tmem141^{p. Trp90*/p. Trp90*} mice. c. After TBS stimulation, the normalized fEPSP slope of the Tmem141^{p. Trp90*/p. Trp90*} mice significantly decreased compared with that of the WT mice (n = 8; P < 0.01). (B) Golgi staining of mouse hippocampal neurons. Different types of dendritic spines are denoted (red arrowheads, stubby; yellow arrowheads, mushroom; blue arrowheads, branched; red asterisks, thin; and blue asterisks, filopodium). Scale bar in a: 50 μm; scale bar in c: 100 μm; scale bars in b and d: 10 μm. (C) Dendritic spine density of hippocampal neurons in Tmem141^{p. Trp90*/p. Trp90*} and Tmem141^WT/WT mice. A total of 18 neurons from three Tmem141^WT/WT and 15 neurons from three Tmem141^{p. Trp90*/p. Trp90*} mice were calculated. (D) Golgi staining of mouse cerebellar Purkinje cells. Scale bars in a and c: 100 μm; scale bars in b and d: 10 μm. (E) Total number of dendritic branches per neuron. (F) Frequencies of dendritic branches in different orders per neuron, indicating fewer primary branches and terminal branches in Tmem141^{p. Trp90*/p. Trp90*} than in WT littermates. A total of 17 neurons from three Tmem141^WT/WT mice and 19 neurons from three Tmem141^{p. Trp90*/p. Trp90*} mice were calculated.

Fig.2 Identification of a biallelic TMEM141 variant in the individual from the family with neurodevelopmental disorders (NDDs). (A) Pedigree of a family with a TMEM141 nonsense variant. The TMEM141 variant cosegregated with the phenotype in this family as an autosomal recessive trait. The arrow indicates the proband, and the asterisks denote the individuals available for genotyping. (B) Facial photographs of IV-2 showing prominent eyes, mild hypertelorism (eyes were covered in consideration of the patient’s privacy), a short nose with a flattened nasal bridge and a broad nasal base, mildly cupped ears, and a downturned upper lip. (C) Representative brain MRI of the proband (IV-2) showing diffuse subtle cerebral and cerebellar atrophy. (D) Schematic representation of the TMEM141 gene and protein structure (top). Sanger sequence chromatograms of the proband and a heterozygous carrier of the TMEM141 variant. Unaffected controls are also shown (bottom). The arrows indicate the sites of the TMEM141 variant. (E) The Trp90 of TMEM141 is evolutionarily conserved among different species. (F) qRT?PCR of the relative TMEM141 mRNA expression in peripheral blood lymphocytes from the proband and independent control. The data are presented as means ± SE (n ≥ 3; P < 0.05). (G) IF staining for TMEM141 (red) and the mitochondrial marker protein ATP5A (green) indicated that the amounts of mutant protein were significantly reduced compared to those of the wild-type TMEM141 although the mutant protein was still located in the mitochondrion. (H) Immunoblotting of protein lysate from HEK293T cells transfected with wild-type or mutant plasmids showed that the mutant TMEM141 levels were reduced to approximately 40% of control levels. The gray intensity was analyzed using ImageJ software. The data are presented as means ± SE (n ≥ 3; P < 0.05).

Fig.3 Expression profiles and location of Tmem141 protein. (A) a. Tmem141 was initially expressed on the ninth day of embryonic development (E9) and reached a stabilized and high level 7 days after birth (P7); b. Immunoblot assays showing Tmem141 was highly expressed in the heart, kidney, brain, and liver and weakly expressed in the muscles, lungs, and spleen in the WT mice at P60; c. In the brain tissue, the cerebellum and hippocampus had the highest expression levels of Tmem141, followed by the cortex, but low expression levels were observed in basal ganglia and the brainstem. Gray intensity was analyzed using ImageJ software (n ≥ 3). (B) IF staining for Tmem141 in the hippocampus, cerebellum, and cerebral cortex. Representative images showing colocalization of Tmem141 with the marker of hippocampal neurons, NeuN (up), and the marker of cerebellar Purkinje cells, calbindin (middle), but not the marker of astrocytes, Gfap (down). Scale bars: 100 μm. The fluorescence integrated density was measured using the Plot Profile tool of ImageJ software. (C) Electron microscopy of HEK293T cells transfected with the TMEM141-APEX plasmid indicated that TMEM141 was exclusively located in the outer mitochondrial membrane. Scale bar: 10 μm.

Fig.4 Impaired motor coordination and learning ability of Tmem141^{p.Trp90*/p.Trp90*} mice. (A) Rotarod test showing that the Tmem141^{p.Trp90*/p.Trp90*} mice exhibited a significant reduction in time spent on the rotarod compared with WT littermates (n = 7; P < 0.01). (B) Step-down passive avoidance test displaying that the Tmem141^{p.Trp90*/p.Trp90*} mice had a significantly decreased step-down latency compared with WT littermates (n = 7; P < 0.05). (C) Morris water maze test. a. Spatial search paths of Tmem141^{p.Trp90*/p.Trp90*} and Tmem141^WT/WT mice on the first day (day 1) and fourth day (day 4) in the hidden platform test. b. Hidden platform test showing that the Tmem141^{p.Trp90*/p.Trp90*} mice exhibited increased latencies to reach the hidden platform compared with WT mice (n = 7; P < 0.001). c. Probe test showing that the Tmem141^{p.Trp90*/p.Trp90*} mice spent less time in the target zone than WT mice (n = 7; P < 0.05). d. Visible test showing that compared with WT mice, Tmem141^{p.Trp90*/p.Trp90*} mice exhibited slightly increased latencies to reach the visible platform (n = 7; P > 0.05). The mice used for behavioral experiments were all 2 months old.

Fig.5 Morphology and bioenergetic function of the mitochondrion were affected by TMEM141 deficiency. (A) Electron microscopy of hippocampal neurons and cerebellar Purkinje cells aberrantly increased, enlarged mitochondria with irregular and swollen crests appeared, internal structures disappeared, and cavitation became prominent in the Tmem141^{p.Trp90*/p.Trp90*} mice. (B) Normalized oxygen consumption rates (OCR) during a mitochondrial stress test for SH-SY5Y cell cultures (NC, wild-type SH-SY5Y cell cultures; MOCK, SH-SY5Y cells infected with empty vector; TMEM141-KD, SH-SY5Y cells infected with TMEM141 shRNA vector). The results were normalized according to the number of cells in the NC group. (C) Relative ATP production of SH-SY5Y cell cultures in three different groups (normalized to the NC group). The results showed that reduced ATP was produced in TMEM141-KD cell cultures (n = 5; P < 0.01). (D) Basal respiration and maximal respiration of SH-SY5Y cell cultures in three different groups indicated weaker respiration in TMEM141-KD cell cultures than in the NC group (n = 5; P < 0.05).

Fig.6 Identification of the DDHD2 deletion variant in the proband with NDDs. (A) IGV displaying the WGS results of IV-2 and WES results of III-1, indicating that the proband (IV-2) harbored a deletion variant from exon 4 to exon 10 of DDHD2. (B) qPCR of an amplicon located in the deletion region, validating the intragenic deletion. The values presented are the means of triplicate determinations ± SE. The unaffected individual (IV-1) was set to 1.0 relative copy number. (C) Amplification of the deletion junction showing cosegregation of the deletion variant with the phenotype in this family. M: marker. C: normal control. (D) Sanger sequence chromatograms and a schematic representation of the DDHD2 deletion breakpoint. The overlapping sequence is highlighted.

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[1]	Yanfei Wang,Yueyue Liu,Hongyun Nie,Xin Ma,Zhigang Xu. Alternative splicing of inner-ear-expressed genes[J]. Front. Med., 2016, 10(3): 250-257.
[2]	Wenjun Xia,Fei Liu,Duan Ma. Research progress in pathogenic genes of hereditary non-syndromic mid-frequency deafness[J]. Front. Med., 2016, 10(2): 137-142.

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